Substituted hexahdryoazepinones and tetrahydrobenzazepinones

ABSTRACT

The present invention relates to novel substituted hexahydroazepinones and tetrahydrobenzazepinones of the formulae ##STR1## wherein R 1 , Z 1 , Z 2 , W 1 , W 2 , Y 1  and Y 2  are as defined below, and to novel intermediates used in the synthesis of such compounds. 
     Such compounds are useful in the treatment and prevention of gastrointestinal disorders, pain and anxiety disorders.

This is a division of application Ser. No. 08/078,125, which was filedon Jun. 16, 1993, now U.S. Pat. No. 5,484,917 and which claims priorityfrom international patent application PCT/US 92/10720, which was filedon Dec. 16, 1992 as a continuation-in-part of application Ser. No.07/825,677, which was filed on Jan. 27, 1992, now abandoned, and fromwhich both international application PCT/US 92/10720, prior applicationSer. No. 08/078,125 and the present application claim priority.

BACKGROUND OF THE INVENTION

The present invention relates to novel substituted hexahydroazepinonesand tetrahydrobenzazepinones, pharmaceutical compositions comprisingsuch compounds and the use of such compounds in the treatment andprevention of central nervous system and gastrointestinal disorders. Thepharmaceutically active compounds of this invention are selective CCK-Breceptor antagonists.

Cholecystokinin (CCK) is a 33-amino acid peptide originally discoveredand characterized in 1971. (See Mutt et al., Biochem. J., 125, 57(1971)). It carries out its biological responses by binding to its tworeceptor types: CCK-A and CCK-B. The CCK-A receptor is located primarilyin the gallbladder and pancreas, and mediates CCK-induced enzymesecretion and gallbladder contraction during a meal. The CCK-B receptoris located in the stomach, where it is involved in acid secretion, andin the brain, where it mediates pain and anxiety responses.

A number of potent and selective non-peptide antagonists for these tworeceptors are known (See M. G. Bock, Drugs of the Future, 16 (7),631-640 (1991) and R. M. Freidinger, Med. Res. Rev., 9, 271-290 (1989)).Merck's L-364,718 (devazepide) is a selective CCK-A antagonist. (SeeO'Neill et al., Brain Res., 534, 287-290 (1990)). This compound,however, has proven not to be clinically useful. Merck's benzodiazepineL-365,260 is a selective CCK-B antagonist that was found to have ananalgesic effect on squirrel monkeys. (See O'Neill et al., Brain Res.,534, 287-290 (1990)). Clarke-Davis' CI-988 is a selective CCK-Bantagonist that was found to reverse the pentagastrin-induced anxiogenicresponse in rats. (See Singh et al., Proc. Nat'l. Acad. Sci., U.S., 88,1130-33 (1991)).

SUMMARY OF THE INVENTION

The present invention relates to compounds of the formula ##STR2##wherein Y¹ and Y² are independently selected from the group consistingof phenyl, thienyl, pyridyl, furyl, pyrimidyl, (C₃ -C₈) straight orbranched alkyl and (C₅ -C₈) cycloalkyl, wherein said phenyl, thienyl,pyridyl, furyl, and pyrimidyl may optionally substituted with one or twosubstituents independently selected from halo (e.g., chloro, fluoro,bromo or iodo), (C₁ -C₆) alkyl, (C₁ -C₆) alkoxy, nitro, amino andtrifluoromethyl, and wherein said cycloalkyl may optionally besubstituted with one or two substituents independently selected from (C₁-C₆) alkyl;

W¹ and W² are independently selected from halo, nitro, amino, (C₁-C₆)alkyl optionally substituted with from one to three fluorine atomsand (C₁ -C₆)alkoxy optionally subsituted with from one to three fluorineatoms;

Z¹ and Z² are independently selected from the group consisting of halo,(C₁ -C₆) alkyl, (C₁ -C₆) thioalkyl, (C₁ -C₆) alkoxy, trifluoromethyl,(C₁ -C₆) carboalkoxy, amino and nitro;

R¹ is phenyl, CO₂ R², SO₂ NR³ R⁶ or CONR⁴ R⁵, wherein said phenyl mayoptionally be substituted with one or two substituents independentlyselected from halo, (C₁ -C₆) alkyl, (C₁ -C₆) alkoxy, nitro, amino andtrifluoromethyl, and wherein R², R³, R⁴, R⁵ and R⁶ are independentlyselected from hydrogen, (C₃ -C₁₂) alkyl and fused, saturated carbocyclicsystems containing two or three rings.

The present invention also relates to the pharmaceutically acceptableacid addition salts of compounds of the formulae I and II. The acidswhich are used to prepare the pharmaceutically acceptable acid additionsalts of the aforementioned base compounds of this invention are thosewhich form non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions, such as the hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, acetate, lactate, citrate, acid citrate, tartrate,bitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate and pamoate [i.e.,1,1'-methylene-bis-(2-hydroxy-3-naphthoate)] salts.

The term "alkyl", as used herein, unless otherwise indicated, includessaturated monovalent hydrocarbon radicals having straight, branched orcyclic moieties or combinations thereof.

The term "halo", as used herein, unless otherwise indicated, includeschloro, fluoro, bromo and iodo.

Preferred compounds of this invention are compounds of the formula Iwherein either both of Y¹ and Y² are phenyl, or one of Y¹ and Y² iscyclohexyl.

Other preferred compounds of this invention are compounds of the formulaII wherein Y¹ is phenyl.

Preferred compounds of the present invention include the following:

N-tert-butyl-2-[3-(3-(3-thiomethylphenyl)ureido)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoate;

3-((3-chlorophenyl)ureido)-7-cyclohexyl-(N-t-butoxycarbonylmethyl)-hexahydroazepin-2-one;

3-((3-tolyl)ureido)-7-cyclohexyl-(N-t-butoxycarbonylmethyl)hexahydroazepin-2-one;

3-((3-chlorophenyl)ureido)-7-cyclohexyl-(N-1-adamantyloxycarbonylmethyl)-hexahydroazepin-2-one;

3-((3-chlorophenyl)ureido)-7-cyclohexyl-(N-2-adamantyloxycarbonylmethyl)-hexahydroazepin-2-one;

3-((3-tolyl)ureido)-7-cyclohexyl-(N-1-adamantyloxycarbonylmethyl)-hexahydroazepin-2-one;

3-((3-tolyl)ureido)-7-cyclohexyl-(N-2-adamantyloxycarbonylmethyl)-hexahydroazepin-2-one;

3-((3-methoxyphenyl)ureido)-7-cyclohexyl-(N-t-butoxycarbonylmethyl)-hexahydroazepin-2-one;

3-((3-methoxyphenyl)ureido)-7-cyclohexyl-(N-1-adamantyloxycarbonylmethyl)-hexahydroazepin-2-one;

3-((3-methoxyphenyl)ureido)-7-cyclohexyl-(N-2-adamantyloxycarbonylmethyl)-hexahydroazepin-2-one;

3-((3-chlorophenyl)ureido)-5,7-diphenyl-(N-t-butoxycarbonylmethyl)-hexahydroazepin-2-one;

3-((3-tolyl)ureido)-5,7-diphenyl-(N-t-butoxycarbonylmethyl)-hexahydroazepin-2-one;

3-((3-methoxyphenyl)ureido)-5,7-diphenyl-(N-t-butoxycarbonylmethyl)-hexahydroazepin-2-one;

3-((3-chlorophenyl)ureido)-5,7-diphenyl-(N-1-adamantyloxycarbonylmethyl)-hexahydroazepin-2-one;

N-tert-butyl-2-[3-(3-(3-chlorophenyl)ureido)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[3-(3-(3-chlorophenyl)ureido)-2-oxo-5-phenyl-8-methyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[3-(3-(3-tolyl)ureido)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[3-(3-(3-methoxyphenyl)ureido)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[3-(3-(3-thiomethylphenyl)ureido)-2-oxo-5-phenyl-2,3,4,5,-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N,N-di(2-propyl)-2-[3-(3-(3-chlorophenyl)ureido)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N,N-di(2-propyl)-2-[3-(3-(3-toly)ureido)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N,N-di(2-propyl)-2-[3-(3-(3-methoxyphenyl)ureido)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N,N-di(2-propyl)-2-[3-(3-(3-thiomethylphenyl)ureido)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[3-(3-(3-chlorophenyl)ureido)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoate;

N-tert-butyl-2-[3-(3-(3-tolyl)ureido)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoate;

N-tert-butyl-2-[3-(3-(3-methoxyphenyl)ureido)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoate;

N-tert-butyl-2-[2-oxo-3-((3-tolyl)ureido)-5,7-diphenylhexahydroazepin-1-yl]-ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-((3-chlorophenyl)ureido)-5,7-diphenylhexahydroazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-((3-methoxyphenyl)ureido)-5,7-diphenylhexahydroazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-((3-trifluoromethylphenyl)ureido)-5,7-diphenylhexahy-droazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-((3-methylthiophenyl)ureido)-5,7-diphenyl-hexahydroa-zepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-((3-cyanophenyl)ureido)-5,7-diphenyl-hexahydroazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-((3-dimethylaminophenyl)ureido)-5,7-diphenyl-hexahydroazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-((3-ethylphenyl)ureido)-5,7-diphenyl-hexahydroazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-(3-tolylureido)-5-phenyl-8-methyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-(3-tolylureido)-5-phenyl-9-methyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-(3-tolylureido)-5-phenyl-7-chloro-2,3,4,5-tetrahydro-1H(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-(3-tolylureido)-5-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-(3-tolylureido)-5-(4-chlorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-(3-tolylureido)-5-(4-methylphenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-(3-tolylureido)-5-(2-fluorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-(3-tolylureido)-5-(3-chlorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-(3-tolylureido)-5-(3,4-dichlorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-(1,1-dimethyl)propyl)-2-[2-oxo-3-((3-tolyl)ureido)-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

(N-(1-methyl)cyclohexyl)-2-[2-oxo-3-((3-tolyl)ureido)-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-(3-tolylureido)-5-cyclohexyl-2,3,4,5-tetrahydro-1H-(1)-benzazepin-1-yl]ethanoicacid amide.

Examples of other compounds of the present invention include:

N-tert-butyl-2-[2-oxo-3-((3-tolyl)ureido)-5-phenyl,7-(3-pyridyl)-hexahydroazepin-1-yl]ethanoic acid amide;

N-tert-butyl-2-[2-oxo-3-((3-tolyl)ureido)-5-phenyl,7-(2-pyridyl)-hexahydroazepin-1-yl]ethanoic acid amide;

N-tert-butyl-2-[2-oxo-3-((3-tolyl)ureido)-5-phenyl,7-(4-pyridyl)-hexahydroazepin-1-yl]ethanoic acid amide;

N-tert-butyl-2-[2-oxo-3-((3-tolyl)ureido)-5-phenyl,7-(3-thienyl)-hexahydroazepin-1-yl]ethanoic acid amide;

N-tert-butyl-2-[2-oxo-3-((3-tolyl)ureido)-5-phenyl,7-(2-thienyl)-hexahydroazepin-1-yl]ethanoic acid amide;

N-tert-butyl-2-[2-oxo-3-((3-tolyl)ureido)-5-phenyl,7-(2-pyrimidyl)-hexahydroazepin-1-yl]ethanoic acid amide;

N-tert-butyl-2-[2-oxo-3-((3-tolyl)ureido)-5-phenyl,7-(4-pyrimidyl)-hexahydroazepin-1-yl]ethanoic acid amide;

N-tert-butyl-2-[2-oxo-3-((3-tolyl)ureido)-5-(3-fluorophenyl),7-phenyl-hexahydroazepin-1-yl]ethanoic acid amide;

N-tert-butyl-2-[2-oxo-3-((3-tolyl)ureido)-5-(4-chlorophenyl),7-phenyl-hexahydroazepin-1-yl]ethanoic acid amide;

N-tert-butyl-2-[2-oxo-3-((3-tolyl)ureido)-5-(3-chlorophenyl),7-phenyl-hexahydroazepin-1-yl]ethanoic acid amide;

N-tert-butyl-2-[2-oxo-3-((3-tolyl)ureido)-5-(3-trifluoromethylphenyl),7-phenyl-hexahydroazepin-1-yl]ethanoic acid amide;

N-tert-butyl-2-[2-oxo-3-((3-tolyl)ureido)-5-(3-tolyl),7-phenyl-hexahydroazepin-1-yl ]ethanoic acid amide;

N-tert-butyl-2-[2-oxo-3-((3-tolyl)ureido)-5-(4-tolyl),7-phenyl-hexahydroazepin-1-yl]ethanoic acid amide;

N-tert-butyl-2-[2-oxo-3-((3-tolyl)ureido)-5-(4-methoxyphenyl),7-phenyl-hexahydroazepin-1-yl]ethanoic acid amide;

N-tert-butyl-2-[2-oxo-3-((3-tolyl)ureido)-5-(3-methoxyphenyl),7-phenyl-hexahydroazepin-1-yl]ethanoic acid amide;

N-tert-butyl-2-[2-oxo-3-((3-tolyl)ureido)-5-(3-pyridyl),7-phenyl-hexahydroazepin-1-yl]ethanoic acid amide;

N-tert-butyl-2-[2-oxo-3-((3-tolyl)ureido)-5-(3-thienyl),7-phenyl-hexahydroazepin-1-yl]ethanoic acid amide;

N-tert-butyl-2-[2-oxo-3-((3-tolyl)ureido)-5-(4-thienyl),7-phenyl-hexahydroazepin-1-yl]ethanoic acid amide;

N-tert-butyl-2-[2-oxo-3-((3-tolyl)ureido)-5-(2-pyridyl),7-phenyl-hexahydroazepin-1-yl]ethanoic acid amide;

N-tert-butyl-2-[2-oxo-3-((3-tolyl)ureido)-5-cyclohexyl,7-phenyl-hexahydroazepin-1-yl]ethanoic acid amide;

N-(1,1-dimethyl)propyl)-2-[2-oxo-3-((3-tolyl)ureido)-5,7-diphenyl-hexahydroazepin-1-yl]ethanoicacid amide;

N-(1,1-dimethyl)benzyl-2-[2-oxo-3-((3-tolyl)ureido)-5,7-diphenyl-hexahydroazepin-1-yl]ethanoicacid amide;

N-(1-methyl)cyclohexyl-2-[2-oxo-3-((3-tolyl)ureido)-5,7-diphenyl-hexahydroazepin-1-yl]ethanoicacid amide;

N-(1-methyl)cyclopentyl-2-[2-oxo-3-((3-tolyl)ureido)-5,7-diphenyl-hexahydroazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-((3-methylaminophenyl)ureido)-5,7-diphenyl-hexahydroaz-epin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-((3-(N-methyl,N-acetyl)ureido)-5-cyclohexyl,7-phenyl-hexahydroazepin-1-yl]ethanoic acid amide;

N-tert-butyl-2-[2-oxo-3-((3-(N-methyl,N-methanesulfonyl))ureido)-5-cyclohexyl,7-phenylhexahydroazepin-1-yl]ethanoic acid amide;

N-tert-butyl-2-[2-oxo-3-((3-diethylaminophenyl)ureido)-5,7-diphenyl-hexahy-droazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-((3-isopropylaminophenyl)ureido)-5,7-diphenyl-hexahyd-roazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-((3-t-butylaminophenyl)ureido)-5,7-diphenyl-hexahydro-azepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-((3-isopropylphenyl)ureido)-5,7-diphenyl-hexahydroazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-((3-t-butylphenyl)ureido)-5,7-diphenyl-hexahydroazepin-1-yl]ethanoicacid amide;

(N-(1,1-dimethyl)benzyl)-2-[2-oxo-3-((3-tolyl)ureido)-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

(N-(1-methyl)cyclopentyl)-2-[2-oxo-3-((3-tolyl)ureido)-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-((3-dimethylaminophenyl)ureido)-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-((3-methylaminophenyl)ureido)-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-((3-(N-methyl,N-acetyl)ureido)-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-((3-(N-methyl,N-methanesulfonyl))ureido)-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-((3-diethylaminophenyl)ureido)-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-((3-isopropylaminophenyl)ureido)-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-((3-t-butylaminophenyl)ureido)-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-((3-isopropylphenyl)ureido)-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-((3-t-butylphenyl)ureido)-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-(3-tolylureido)-5-phenyl-8-methoxy-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-(3-tolylureido)-5-phenyl-8-ethyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-(3-tolylureido)-5-phenyl-8-fluoro-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-(3-tolylureido)-5-phenyl-8-chloro-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-(3-tolylureido)-5-phenyl-7-methoxy-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-(3-tolylureido)-5-phenyl-7-fluoro-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-(3-tolylureido)-5-phenyl-7-trifluoromethyl-2,3,4,5-tetra-hydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-(3-tolylureido)-5-phenyl-8-trifluoromethyl-2,3,4,5-tetra-hydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-(3-tolylureido)-5-(3-fluorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-(3-tolylureido)-5-(3-trifluoromethylphenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-(3-tolylureido)-5-(4-trifluoromethylphenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-(3-tolylureido)-5-(3-dimethylaminophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-(3-tolylureido)-5-(3-sulfonamidophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-(3-tolylureido)-5-(3-(acetylamino)phenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-(3-tolylureido)-5-(3,4-difluorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-(3-tolylureido)-5-(3,4-dimethylphenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-(3-ethylphenylureido)-5-(4-chlorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-(1,1-dimethylpropyl)-2-[2-oxo-3-(3-tolylureido)-5-(4-chlorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-(3-dimethylaminophenylureido)-5-(4-chlorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-(3-dimethylaminophenylureido)-5-(4-methylphenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-(1,1-dimethylpropyl)-2-[2-oxo-3-(3-tolylureido)-5-(4-methylphenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-(3-ethylphenylureido)-5-(4-chlorophenyl)-8-methyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-(1,1-dimethylpropyl)-2-[2-oxo-3-(3-tolylureido)-5-(4-chlorophenyl)-8-methyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-(3-dimethylaminophenylureido)-5-(4-chlorophenyl)-9-methyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-tert-butyl-2-[2-oxo-3-(3-dimethylaminophenylureido)-5-(4-methylphenyl)-8-chloro-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-(1,1-dimethylpropyl)-2-[2-oxo-3-(3-tolylureido)-5-(4-methylphenyl)-8-chloro-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-(1,1-dimethylpropyl)-2-[2-oxo-3-(3-ethylphenylureido)-5-(4-methylphenyl)-8-chloro-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-(1,1-dimethylpropyl)-2-[2-oxo-3-(3-dimethylaminophenylureido)-5-(4-methylphenyl)-8-chloro-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-(1,1-dimethylpropyl)-2-[2-oxo-3-(3-dimethylaminophenylureido)-5-(4-chlorophenyl)-8-chloro-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-(1,1-dimethylpropyl)-2-[2-oxo-3-(3-tolylureido)-5-(4-methylphenyl)-8-methyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-(1,1-dimethylpropyl)-2-[2-oxo-3-(3-ethylphenylureido)-5-(4-chlorophenyl)-8-methyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N-(1,1-dimethylpropyl)-2-[2-oxo-3-(3-dimethylaminophenylureido)-5-(4-chlorophenyl)-8-methyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N,N-di(tert-butyl-2-[3-(3-(chlorophenyl)ureido)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N,N-di(tert-butyl)-2-[3-(3-tolyl)ureido)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

N,N-di(tert-butyl)2-[3-(3-(methoxyphenyl)ureido)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide;

3-((3-chlorophenyl)ureido)-7-(2,6-dimethylcyclohexyl)-(N-t-butoxycarbonylmethyl)-hexahydroazepin-2-one;

3-((3-tolyl)ureido)-7-(2,6-dimethylcyclohexyl)-(N-t-butoxycarbonylmethyl)-hexahydroazepin-2-one;

3-((3-methoxyphenyl)-7-(2,6-dimethylcyclohexyl)-(N-t-butoxycarbonylmethyl)-hexahydroazepin-2-one;

3-((3-methoxyphenyl)ureido)-5-phenyl-7-cyclohexyl-(N-1-adamantylcarbonylmethyl)-hexahydroazepin-2-one;

3-((3-methoxyphenyl)ureido)-5-phenyl-7-cyclohexyl-(N-2-adamantylcarbonylmethyl)-hexahydroazepin-2-one;

3-((3-tolyl)ureido)-5-phenyl-7-cyclohexyl-(N-1-adamantyloxycarbonylmethyl)-hexahydroazpin-2-one;

3-((3-tolyl)ureido)-5-phenyl-7-cyclohexyl-(N-2-adamantyloxycarbonylmethyl)-hexahydroazepin-2-one;

3-((3-chlorophenyl)ureido)-5-phenyl-7-cyclohexyl-(N-1-adamantyloxycarbonylmethyl)-hexahydroazepin-2-one;and

3-((3-chlorophenyl)ureido)-5-phenyl-7-cyclohexyl-(N-2-adamantyloxycarbonylmethyl)-hexahydroazepin-2-one.

This invention also relates to compounds of the formula ##STR3## whereinR⁷ is hydrogen or one of the radicals set forth in the definition of R¹above, R⁸ is bromine, amino or azido and Y¹, W¹ and W² are defined asabove. These compounds are useful as intermediates in the synthesis ofcompounds of the formula II.

The present invention also relates to a pharmaceutical composition fortreating or preventing a condition selected from the group consisting ofpain, gastrointestinal disorders such as ulcer and colitis, and centralnervous system disorders such as anxiety and panic disorder in a mammal,including a human, comprising an amount of a compound of the formula Ior II, or a pharmaceutically acceptable salt thereof, effective intreating or preventing such condition, and a pharmaceutically acceptablecarrier.

The present invention also relates to a method of treating or preventinga condition selected from the group consisting of pain, gastrointestinaldisorders such as ulcer and colitis, and central nervous systemdisorders such as anxiety and panic disorder in a mammal, including ahuman, comprising administering to said mammal an amount of a compoundof the formula I or II, or a pharmaceutically acceptable salt thereof,effective in treating or preventing such condition.

The present invention also relates to a pharmaceutical composition forantagonizing the effects of cholecystokinin in a mammal, including ahuman, comprising a cholecystokinin antagonizing amount of a compound ofthe formula I or II, or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier.

The present invention also relates to a method of antagonizing theeffects of cholecystokinin in a mammal, including a human, comprisingadministering to said mammal a cholecystokinin antagonizing amount of acompound of the formula I or II, or a pharmaceutically acceptable saltthereof.

The present invention also relates to a pharmaceutical composition fortreating or preventing a cholecystokinin mediated disorder in a mammal,including a human, comprising a cholecystokinin antagonizing amount of acompound of the formula I or II, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.

The present invention also relates to a method of treating or preventinga cholecystokinin medicated disorder in a mammal, including a human,comprising administering to said mammal a cholecystokinin antagonizingamount of a compound of the formula I or II, or a pharmaceuticallyacceptable salt thereof.

The present invention also relates to a pharmaceutical composition fortreating or preventing a condition selected from the group consisting ofpain, gastrointestinal disorders such as ulcer and colitis, and centralnervous system disorders such as anxiety and panic disorder in a mammal,including a human, comprising an amount of a compound of the formula Ior II, or a pharmaceutically acceptable salt thereof, effective inantagonizing the effect of cholecystokinin at its receptor site, and apharmaceutically acceptable carrier.

The present invention also relates to a method of treating or preventinga condition selected from the group consisting of pain, gastrointestinaldisorders such as ulcer and colitis, and central nervous systemdisorders such as anxiety and panic disorder in a mammal, including ahuman, comprising administering to said mammal an amount of a compoundof the formula I or II, or a pharmaceutically acceptable salt thereof,effective in antagonizing the effect of cholecystokinin at its receptorsite.

The compounds of the formulae I and II have chiral centers and thereforeexist in different enantiomeric and diastereomic forms. This inventionrelates to all optical isomers and all stereoisomers of compounds of theformulae I and II, and mixtures thereof.

Formula I and formula II above include compounds identical to thosedepicted but for the fact that one or more hydrogen or carbon atoms arereplaced by isotopes thereof. Such compounds are useful as research anddiagnostic tools in metabolism pharmacokinetic studies and in bindingassays.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the formulae I and II may be prepared as described inthe following reaction schemes and discussion. Unless otherwiseindicated, R¹, R², R³, R⁴, R⁵, R⁶, Y¹, Y², Z¹, Z², W¹ and W² in thereaction schemes and discussion that follow are defined as above.##STR4##

The preparation of compounds of the formula I wherein R¹ is CO₂ R², C₆H₅, CONR⁴ R⁵ or SO₂ NR³ R⁶ (hereinafter referred to as compounds of theformula IA) is illustrated in scheme 1.

Referring to scheme 1, a compound of the formula III is reacted withhydroxylamine hydrochloride in methanol in the presence of sodiumbicarbonate or triethylamine, to form a compound of the formula IV. Thisreaction is generally carried out at a temperature from about roomtemperature to about the reflux temperature of the reaction mixture. Thecompound of formula IV so formed is then converted to a compound of theformula V by reacting it with tosyl chloride in pyridine at about 0° C.for about 24 hours.

Alternatively, compounds of the formula III may be converted directlyinto the corresponding compounds having formula V in a one stepprocedure. According to this procedure, a compound of the formula III isreacted with NH₂ OSO₃ H (hydroxylamine-O-sulfonic acid) in formic acidat about the reflux temperature of the reaction mixture. This one stepprocedure is preferred over the two step procedure described above forall compounds of the formula IV except those wherein Y¹ is phenyl andadjacent to the oxo group.

Bromination of the compound of formula V yields the correspondingcompound having formula VI. The bromination is typically carried out byfirst adding a compound of the formula V to a mixture of phosphoruspentachloride and pyridine in methylene chloride at about 0° C. Then,phenyltrimethylammonium bromide tribromide is added to the reactionmixture, also at a temperature of about 0° C. Alternatively, the secondstep, which involves the addition of the brominating agent, may bereplaced by a procedure in which bromine is added at a temperature ofabout 0° C. and allowed to react for a period of about 0.5 hours toabout 5 hours, preferably about 2 hours, resulting in dibromination ofthe saturated nitrogen containing seven membered ring. One of thebromine atoms is then selectively removed by treatment with hydrogen gasin the presence of palladium which has been poisoned with quinoline.

The brominated compound of formula VI is then alkylated at the ringnitrogen by reaction with a compound of the formula XCH₂ R¹, wherein Xis bromine when R¹ is phenyl and X is iodine for all other R¹, intetrahydrofuran (THF) in the presence of sodium hydride. This reaction,which yields the corresponding compound of formula VII, is usuallyconducted at a temperature from about room temperature to about 150° C.It is preferably conducted at the reflux temperature of the reactionmixture.

The compound of formula VII formed in the above step is then reactedwith an alkali metal azide to produce a compound of the formula VIII.The preferred reactant is sodium azide. Generally, this reaction iscarried out in a reaction inert solvent such as dimethylformamide (DMF)or dimethylsulfoxide (DMSO), preferably DMF, at a temperature from about60° C. to about 100° C., preferably about 80° C.

Reduction of the azide of formula VIII yields the corresponding amine offormula IX. The reduction is typically accomplished using hydrogen gasat a pressure of from about 1 to about 3 atmospheres in the presence ofpalladium on carbon (Pd/C). Suitable reaction inert solvents includehalogenated hydrocarbons and (C₁ -C₆) alkanols. Ethanol is the preferredsolvent. The reaction temperature may range from about 15° C. to about70° C., with about room temperature being preferred.

Alternatively, the reduction may be accomplished using a trialkyl ortriaryl phosphine. Examples of appropriate reactants aretriphenylphosphine and tributylphosphine. This reaction is generallyconducted in a reaction inert solvent such as THF or another etherealwater miscible solvent in the presence of water, at a temperature fromabout room temperature to about 100° C. Preferably, it is conducted inTHF at about room temperature.

The compound of formula IX so formed is then converted into thecorresponding compound having formula IA by reacting it with anisocyanate of the formula C₆ H₄ Z¹ Z² NCO. Appropriate reaction inertsolvents for this reaction include hydrocarbons such as hexane, benzeneand toluene, halogenated hydrocarbons such as methylene chloride and1,2-dichloroethane, ethereal solvents such as ethyl ether, THF andglyme, and pyridine. The preferred solvent is 1,2-dichloroethane ormethylene chloride. Tertiary organic amines may be useful as catalysts.The reaction temperature may range from about 0° C. to about 150° C. Thereflux temperature is preferred.

The isocyanate of the formula C₆ H₄ Z¹ Z² NCO used in the foregoingreaction can be formed by procedures well known to those skilled in theart. One such method involves mixing a benzoic acid derivative withdiphenylphosphorylazide, or an analagous reagent, in the presence of anorganic base such as a trialkylamine, preferably triethylamine ordiisopropylethylamine. This reaction is usually conducted in anethereal, hydrocarbon or chlorinated hydrocarbon solvent, preferablytetrahydrofuran or benzene, at a temperature from about room temperatureto about 100° C., preferably at the reflux temperature of the solvent,for a period from about 20 minutes to about 24 hours, preferably about 1hour.

Scheme 2 illustrates the synthesis of compounds of the formula I whereinR¹ is CO₂ H (hereinafter referred to as compounds of the formula IB)from compounds of the formula IA wherein R¹ is CO₂ R². It alsoillustrates a method of preparing compounds of the formula IA wherein Ris an amide (i.e., R¹ is CONR⁴ R⁵) from the corresponding acids offormula IB.

Referring to scheme 2, hydrolysis of a compound of the formula IAwherein R¹ is CO₂ R² yields the corresponding acid of formula IB. Thehydrolysis is typically carried out using trifluoroacetic acid in areaction inert solvent as hexane, an ethereal solvent (e.g., ethyl etheror THF) or a halogenated hydrocarbon solvent (e.g., methylene chlorideor 1,2-dichloroethane), at a temperature from about -78° C. to about 50°C. It is preferably carried out using trifluoroacetic acid in ahalogenated hydrocarbon cosolvent at about 0° C.

The acid of formula IB may be converted into the corresponding amide offormula IA, wherein R¹ is CONR⁴ R⁵, by reacting the acid with an amineof the formula NHR⁴ R⁵ in the presence of a dehydrating agent. Thedehydrating agent is preferably a carbodiimide. Other dehydrating agentsthat may be used are 1,1'-carbonyldiimidazole andisobutylchloroformate/N-methylmorpholine. This reaction is generallyconducted in a reaction inert solvent selected from hydrocarbons such asbenzene, toluene and hexane, halogenated hydrocarbons such as methylenechloride and 1,2-dichloroethane, ethereal solvents such as ethyl ether,THF and glyme, and pyridine, preferably THF, at a temperature from about0° C. to about 120° C., preferably at about room temperature.

Scheme 3 illustrates the preparation of compounds of the formula IIwherein R¹ is CO₂ R², C₆ H₅, CONR⁴ R⁵ or SO₂ NR³ R⁶ (hereinafterreferred to as compounds of the formula IIA).

Referring to scheme 3, a compound of the formula X is converted into thecorresponding compound of formula XII by the following two stepprocedure. First, the compound of formula X is converted into an oximeby the method described above and illustrated in scheme 1 for formingcompounds of the formula IV from compounds of the formula III. Then,rearrangement of the oxime to form the lactam having formula XI isaccomplished by reacting the oxime with polyphosphoric acid. Thisreaction may be carried out at temperatures ranging from about roomtemperature to about 200° C. Preferably, the reaction mixture is heatedto about 160° C.

The resulting compound of formula XI is then brominated to form acompound of the formula XII by first reacting it with phosphorouspentachloride and pyridine, and then adding bromine. The reaction withphosphorus pentachloride and pyridine is conducted as described abovefor the first step in the bromination of compounds of the formula V. Thereaction with bromine, which results in monobromination, is carried outat a temperature from about -78° C. about 0° C., preferably at about-40° C.

Alkylation of the compound of formula XII yields the correspondingcompound of formula XIII. The alkylation is carried out by reacting thecompound of formula XII with a compound of the formula XCH₂ R¹, whereinX is bromine when R¹ is phenyl and X is iodine for all other R¹, inTHF/DMSO in the presence of lithium dialkylamide. It is preferable toadd the DMSO cosolvent after adding the lithium dialkylamide. Thereaction temperature may range from about -78° C. to about 0° C. duringaddition of the base, and is preferably about -78° C. The reaction isslowly warmed to a temperature from about -20° C. to about 50° C. whenthe DMSO is added. Preferably, the reaction is warmed to about roomtemperature during addition of DMSO.

The conversion of compounds of the formula XIII formed by the foregoingprocedure into the corresponding compounds of the formula IIA by thereaction sequence XIII→XIV→XV→IIA depicted in scheme 3 in carried out bythe method described above for the analogous reaction stepsVII→VIII→IX→IA depicted in scheme 1.

Compounds of the formula II wherein R¹ is CO₂ H may be prepared, andcompounds of the formula II wherein R¹ is CONR⁴ R⁵ may be prepared,alternatively, by the procedure depicted in scheme 2 and described aboveforming the analogous compounds of formula I.

The starting materials used in the procedures of schemes 1 and 3 areeither commercially available, known in the art or readily obtainableform known compounds by methods that will be apparent to those skilledin the art.

The preparation of other compounds of the formulae I and II notspecifically described in the foregoing experimental section can beaccomplished using combinations of the reactions described above thatwill be apparent to those skilled in the art.

In each of the reactions discussed or illustrated in schemes 1 to 3above, pressure is not critical unless otherwise indicated. Pressuresfrom about 0.5 atmospheres to about 5 atmospheres are generallyacceptable, and ambient pressure, i.e. about 1 atmosphere, is preferredas a matter of convenience.

The compounds of the formulae I and II (the active compounds of thisinvention) which are basic in nature are capable of forming a widevariety of different salts with various inorganic and organic acids.Although such salts must be pharmaceutically acceptable foradministration to animals, it is often desirable in practice toinitially isolate a compound of the formula I or II from the reactionmixture as a pharmaceutically unacceptable salt and then simply convertthe latter back to the free base compound by treatment with an alkalinereagent and subsequently convert the latter free base to apharmaceutically acceptable acid addition salt. The acid addition saltsof the active base compounds of this invention are readily prepared bytreating the base compound with a substantially equivalent amount of thechosen mineral or organic acid in an aqueous solvent medium or in asuitable organic solvent, such as methanol or ethanol. Upon carefulevaporation of the solvent, the desired solid salt is readily obtained.

The active compounds of this invention and their pharmaceuticallyacceptable salts are useful as selective CCK-B receptor antagonists,i.e., they possess the ability to antagonize the effects of CCK at its Breceptor site in mammals, and therefore they are able to function astherapeutic agents in the treatment of the aforementioned disorders anddiseases in an afflicted mammal.

The active compounds of this invention and their pharmaceuticallyacceptable salts can be administered via either the oral, parenteral ortopical routes. In general, these compounds are most desirablyadministered in dosages ranging from about 5.0 mg up to about 1500 mgper day, although variations will necessarily occur depending upon theweight and condition of the subject being treated and the particularroute of administration chosen. However, a dosage level that is in therange of about 0.07 mg to about 21 mg per kg of body weight per day ismost desirably employed. Variations may nevertheless occur dependingupon the species of animal being treated and its individual response tosaid medicament, as well as on the type of pharmaceutical formulationchosen and the time period and interval at which such administration iscarried out. In some instances, dosage levels below the lower limit ofthe aforesaid range may be more than adequate, while in other casesstill larger doses may be employed without causing any harmful sideeffect, provided that such larger doses are first divided into severalsmall doses for administration throughout the day.

The active compounds of the invention may be administered alone or incombination with pharmaceutically acceptable carriers or diluents byeither of the three routes previously indicated, and such administrationmay be carried out in single or multiple doses. More particularly, thenovel therapeutic agents of this invention can be administered in a widevariety of different dosage forms, i.e., they may be combined withvarious pharmaceutically acceptable inert carriers in the form oftablets, capsules, lozenges, troches, hard candies, powders, sprays,creams, salves, suppositories, jellies, gels, pastes, lotions,ointments, aqueous suspensions, injectable solutions, elixirs, syrups,and the like. Such carriers include solid diluents or fillers, sterileaqueous media and various non-toxic organic solvents, etc. Moreover,oral pharmaceutical compositions can be suitably sweetened and/orflavored. In general, the therapeutically-effective compounds of thisinvention are present in such dosage forms at concentration levelsranging from about 5.0% to about 70% by weight.

For oral administration, tablets containing various excipients such asmicrocrystalline cellulose, sodium citrate, calcium carbonate, dicalciumphosphate and glycine may be employed along with various disintegrantssuch as starch (and preferably corn, potato or tapioca starch), alginicacid and certain complex silicates, together with granulation binderslike polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often very useful for tabletting purposes. Solid compositionsof a similar type may also be employed as fillers in gelatin capsules;preferred materials in this connection also include lactose or milksugar as well as high molecular weight polyethylene glycols. Whenaqueous suspensions and/or elixirs are desired for oral administration,the active ingredient may be combined with various sweetening orflavoring agents, coloring matter or dyes, and, if so desired,emulsifying and/or suspending agents as well, together with suchdiluents as water, ethanol, propylene glycol, glycerin and various likecombinations thereof.

For parenteral administration, solutions of an active compound of thepresent invention in either sesame or peanut oil or in aqueous propyleneglycol may be employed. The aqueous solutions should be suitablybuffered (preferably pH greater than 8) if necessary and the liquiddiluent first rendered isotonic. These aqueous solutions are suitablefor intravenous injection purposes. The oily solutions are suitable forintraarticular, intramuscular and subcutaneous injection purposes. Thepreparation of all these solutions under sterile conditions is readilyaccomplished by standard pharmaceutical techniques well known to thoseskilled in the art.

Additionally, it is also possible to administer the active compounds ofthe present invention topically when treating inflammatory conditions ofthe skin and this may preferably be done by way of creams, jellies,gels, pastes, ointments and the like, in accordance with standardpharmaceutical practice.

The activity of the compounds of the present invention as CCK-Bantagonists may be determined by an assay that measures their ability toinhibit the binding of 125-I-BH-CCK-8 to the CCK-B receptor in a guineapig cortical membrane preparation. This procedure is carried out asfollows. The cortex is dissected from one male Hartley Guinea pig andhomogenized (15 strokes) with a teflon homogenizer in 20 volumes (w./v.)of the assay buffer, which consists of 50 mM Tris (i.e., trimethamine,which is 2-amino-2-hydroxymethyl-1,3-propanediol) hydrochloric acidhaving pH 7.4 and 5 mM of manganese chloride at 4° C. The homogenate iscentrifuged at 4° C. for 30 minutes at 100,000×G. The pellet isresuspended in the same buffer and spun as described above. The finalpellet is diluted to a concentration of 20 mg/ml with the assay bufferfor use in the binding assay. The tissue is kept on ice at all times.

An incubation mixture is prepared, which consists of 50 uL of the tissuepreparation, prepared as described above, 100 uL 125-I-BH-CCK-8 (to givea concentration of 50 pM in the final assay), 20 uL of a blank or thecompound being tested, and 30 uL of Tris with 4% DMSO. All drugs anddilutions are made using 4% DMSO in the assay buffer yielding a finalassay DMSO concentration of 1%.

The reaction is initiated with the addition of tissue to a 96-well platecontaining 125-I-BH-CCK-8 and the appropriate blank or compound beingtested. Non-specific binding is estimated using 1 uM sulphated CCK-8.The reaction is terminated by spinning the plates in a H1000B rotorfitted on a Sorvall RT6000 refrigerated centrifuge at 4° C. Thesupernatant is discarded, and the pellets washed with 200 uL of assaybuffer, and the plate is spun as above. The supernatant is decantedagain, and the pellet is harvested onto Betaplate filters (which havebeen soaked in 0.2% polyethyleneimine for a minimum of 2 hours) using aSkatron cell harvester at setting 222 using Tris HCl pH 7.4 as the washbuffer. The filtermats are counted on a Betaplate counter for 45 secondsper sample.

Data are expressed as IC₅₀ values (the concentration which inhibits 50%of the specific binding of 125-I-BH-CCK-8). The data is analyzed usingnon-linear regression analysis.

The present invention is illustrated by the following examples. It willbe understood, however, that the invention is not limited to thespecific details of these examples.

EXAMPLE 1N-tert-butyl-2-[3-(3-(3-tolyl)ureido)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

A. 3-Bromo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one

To a 125 ml round-bottomed flask containing PCl₅ (1.041 g, 5 mmoles)dissolved in 50 ml methylene chloride under nitrogen in an ice/acetonebath was added 5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (1.187g, 5 mmoles). A slight temperature rise was noted, and then pyridine(0.42 ml, 5.25 mmoles) in 5 ml methylene chloride was added rapidlydropwise. The mixture was stirred for 15 minutes. and then cooled to-45° C. Bromine (0.258 ml, 5 mmoles) in 7 ml methylene chloride was thenadded dropwise over 30 minutes. with rapid stirring. The bath wasremoved after 15 minutes. and the mixture was allowed to come to roomtemperature. Thin layer chromatography (TLC) (silica gel, 23:2,methylene chloride:ethyl acetate) showed no starting material, only anon-polar intermediate (iminochloride). The remainder of the reactionwas diluted with an equal volume of tetrahydrofuran and 200 ml wateradded. This mixture was stirred for 40 minutes, then separated. Theaqueous layer was re-extracted with methylene chloride and the combinedorganic fractions washed with water, dried with brine and sodiumsulfate, filtered, and evaporated yielding 1.56 g (98.7%) of crudeproduct.

The diastereomeric bromides (R_(f) =0.57, and 0.48) may be separated bychromatography or crystallized from ether and hexane; however, themixture was used directly in the next step (B).

The solid obtained by crystallization was predominately the more polarisomer while the mother liquor contained more of the less polar isomeras well as traces of the iminochloride and starting material.Recrystallization of the more polar diastereomer from chloroform gavelarge crystals, mp 191°-192° C.:

¹ H-NMR (δ, CDCl₃): 2.92 (m, 1H), 3.14 (m, 1H), 4.49 (m, 1H), 4.63 (m,1H), 6.77 (d, 1H), 7.09 (m, 3H), 7.32 (m, 6H), 7.85 (bs, 1H).

MS (%): 315/317 (parent for Br⁷⁹ /Br⁸¹, 20/18) 236 (78), 208 (100), 194(36), 180 (73), 130 (47), 115 (39), 91 (79).

B. t-Butyl2-[3-bromo-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoate

To a 125 ml three-neck round bottomed flask equipped with septum and N₂inlet were added3-bromo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (3.216 g,10.17 mmoles) and 50 ml dry tetrahydrofuran (THF) under nitrogen. Thereaction was cooled in a dry ice bath, and lithium bis-trimethylsilylamide (11.2 ml of 1M in THF) was added slowly. The mixture was stirredfor 5 minutes. T-butyl iodoacetate (2.708 g, 11.19 mmoles) was thenadded. The bath was removed and 25 ml of dimethylsulfoxide (DMSO) wasadded at -20° C. After one hour at room temperature, an acidifiedaliquot showed only a trace of starting material by TLC (24:1, CH₂ Cl₂:EtOAc). The reaction mixture was poured into ice water and ethylacetate containing 25 ml of N HCl, stirred for 5 minutes. and separated.The ethyl acetate extraction was repeated and the combined extractswashed three times with water, dried with brine and sodium sulfate, andfiltered and evaporated, yielding 4.9 g (>100%, still containing tracesof solvent) crude product.

Similarly, the lactam was alkylated with N-tert-butyl iodoacetamide toyieldN-t-Butyl-2-[3-bromo-2-oxo-5-phenyl-2,3,4,5,-tetrahydro-1H-(1)benzazepin-1-yl]-ethanoicacid amide.

C.N-tert-butyl-2-[3-azido-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

To a 250 ml round-bottomed flask equipped with N₂ inlet were addedN-tert-butyl-2-[3-bromo-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide, (8.317 g, 19.37 mmoles), 90 ml dimethylformamide (DMF), andsodium azide (5.25 g, 80 mmoles, under nitrogen), and the mixture washeated at 75° C. for 20 hours with stirring. The reaction mixture wasthen cooled and distributed between water and ethyl acetate, separated,and the aqueous phase was again extracted. The combined extracts werewashed with water three times, with bicarbonate solution once, and thendried with brine and sodium sulfate and filtered and evaporated, leavinga gummy residue, 8.58 g (100%), containing some solvent.

¹ H-NMR (δ, CDCl₃): 1.48 (s, 9H), 2.88 (m, 2H), 4.52 (AB quartet, J_(AB)=17, Δγ=138, 2H), 4.57 (m, 1H), 5.06 (m, 1H), 6.73 (d, 1H), 7.26 (m,8H).

D.N-tert-butyl-2-[3-amino-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

The crude product from the previous displacement reaction,N-tert-butyl-2-[3-azido-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide, (8.58 g, 19.37 mmoles), was dissolved in 75 ml methanolunder nitrogen. The catalyst, 6 g of 5% Pd/C, 50% w/w, was added and themixture was hydrogenated at 55 psi H₂ for 5 hours. The mixture wasfiltered through Celite®and the catalyst washed three times withmethanol and the filtrate evaporated. TLC (24:1, methylene chloride:methanol, silica gel), showed less polar material and the product atR_(f) =0.25. The crude product taken up in ethyl acetate and extractedwith acid. The acidic extract was back washed with ethyl acetate andthen the aqueous fraction was taken with fresh ethyl acetate and the pHadjusted to 10.0. The organic fraction was then dried with brine andsodium sulfate, filtered and concentrated, yielding 1.832 g (25.8%) ofthe crystalline amine (mp 189°-192° C., one diastereomer). The motherliquor yielded 1.545 g (21.8%) of a foam upon stripping the solvent,which contained nearly a 1:1 mixture of the diastereomers.

¹ H-NMR (δ, CDCl₃): 1.30 (s, 9H), 2.2 (bs, 2H), 3.06 (AB quartet, J_(AB)=15, Δγ=276, 2H), 2.67 (m, 1H), 2.84 (m, 1H), 3.57 (m, 1H), 4.18 (m,1H), 6.01 (bs, 1H), 7.2 (m, 9H).

E.N-tert-butyl-2-[3-(3-(3-tolyl)ureido)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

To a 25 ml round-bottomed flask equipped with N₂ inlet were addedN-tert-butyl-2-[3-amino-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide (0.50 g, 1.368 mmoles) and 10 ml methylene chloride undernitrogen, and the reaction cooled in an ice bath. A solution of m-tolylisocyanate (0.194 ml, 1.5 mmol) in 5 ml methylene chloride was thenadded dropwise. A solid formed immediately. Stirring was continued for15 minutes and then the ice bath removed, allowing the reaction to cometo room temperature for several hours. The solid was filtered and washedwith methylene chloride/hexane (1:1), yielding 600 mg (87.9%) ofproduct, mp 263°-266° C.

NMR (δ, DMSO-d₆): 1.23 (s, 9H), 2.21 (s, 3H), 2.54 (m, 1H), 2.9 (m, 1H),3.34 (AB quartet, J_(AB) =16, Δγ=255, 2H), 3.4 (HOD peak), 4.34 (m, 2H),6.8 (m, 2H), 7.3 (m, 11H), 8.78 (s, 1H).

The title compounds of Examples 2 through 10 were prepared using aprocedure analogous to that of Example 1.

EXAMPLE 2tert-butyl-2-[3-(3-(4-chlorophenyl)ureido)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoate

Prepared in 30% yield after chromatography and crystallization, M.P.148°-150° C.

¹ H-NMR (δ, CDCl₃): 1.37 (s, 9H), 2.8-3.1 (m, 2H), 3.30 (AB quartet,J_(AB) =17, Δν=188, 2H), 4.27 (m, 1H), 4.76 (m, 1H), 6.8 (broad s, 1H),7.0-7.5 (m, 14H).

MS (%): 520 (18, parent), 366 (35), 337 (43), 267 (70), 206 (85), 153(76), 127 (100), 91 (53).

HRMS calc'd for C₂₉ H₃₁ N₃ O₄ Cl: 520.2003. Found: 520.1983.

EXAMPLE 3N-tert-butyl-2-[3-(3-(3-chlorophenyl)ureido)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared in 90% yield, mp 264°-266° C.

¹ H-NMR (δ, DMSO-d₆): 1.21 (s, 9H), 2.56 (m, 1H), 2.9 (m, 1H), 3.35 (ABquartet, J_(AB) =17, Δν=255, 2H), 4.37 (m, 2H), 6.7-7.6 (m, 14H), 9.08(s, 1H).

MS (%): 518 (1, parent), 322 (40), 194 (60), 91 (70), 58 (100).

HRMS calc'd for C₂₉ H₃₁ N₄ O₃ Cl: 518.2097. Found: 518.2100.

EXAMPLE 4N-tert-butyl-2-[3-(3-(2-tolyl)ureido)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared in 85% yield, mp 231°-233° C.

¹ H-NMR (δ, CDCl₃): 1.28 (s, 9H), 2.24 (s, 3H), 2.65 (m, 1H), 3.09 (ABquartet J_(AB) =17, Δν=291, 2H), 3.11 (m, 1H), 4.22 (m, 1H), 4.62 (m,1H), 6.01 (broad s, 1H), 6.41 (broad s, 1H), 6.9-7.5 (m, 13H).

MS (%): 498 (0.5, parent), 322 (5), 249 (8), 133 (80), 105 (100), 78(80).

HRMS calc'd for C₃₀ H₃₄ N₄ O₃ : 498.2630. Found: 498.25475.

EXAMPLE 5N-tert-butyl-2-[3-(3-(3-methoxyphenyl)ureido)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared in 81% yield, mp 254°-257° C.

¹ H-NMR (δ, DMSO-d₆): 1.21 (s, 9H), 2.56 (m, 1H), 2.9 (m, 1H), 3.33 (ABquartet, J_(AB) =16, Δν=259, 2H), 4.35 (m, 2H), 6.4-7.6 (m, 14H), 8.865(broad s, 1H).

MS (%): 514 (0.1, parent), 322 (6), 149 (100), 106 (40).

HRMS calc'd for C₃₀ H₃₄ N₄ O₄ : 514.2553. Found: 514.26134.

EXAMPLE 6N-tert-butyl-2-[3-(3-(4-chlorophenyl)ureido)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared in 88% yield, mp 247°-249° C.

¹ H-NMR (δ, CDCl₃): 1.31 (s, 9H), 2.92 (m, 1H), 3.10 (m, 1H), 3.22 (ABquartet, J_(AB) =16, Δν=260, 2H), 4.29 (m, 1H), 4.60 (m, 1H), 5.74(broad s, 1H), 6.43 (broad s, 1H), 7.0-7.5 (m, 13H).

MS (%): 518 (1, parent), 322 (40), 261 (70), 153 (100).

HRMS calc'd for C₂₉ H₃₁ N₄ O₃ Cl: 518.2070. Found: 518. 21007.

EXAMPLE 7N-tert-butyl-2-[3-(3-(4-tolyl)ureido)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared in 95% yield, mp 235°-238° C.

¹ H-NMR (δ, CDCl₃): 1.29 (s, 9H), 2.27 (s, 3H), 2.72 (m, 1H), 3.12 (m,1H), 3.25 (AB quartet, J_(AB) =16, Δν=283, 2H), 4.24 (m, 1H), 4.60 (m,1H), 5.88 (broad s, 1H), 6.8-7.4 (m, 14H).

MS (%): 498 (1, parent), 322 (30), 249 (15), 221 (20), (20), 133 (100).

HRMS calc'd for C₃₀ H₃₄ N₄ O₃ : 498.2646. Found: 498.26153.

EXAMPLE 8N-tert-butyl-2-[3-(3-trifluoromethylphenyl)ureido-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared in 67% yield, mp 135°-139° C.

¹ H-NMR (δ, CDCl₃): 1.30 (s, 9H), 3.1 (m, 2H), 3.31 (AB quartet, J_(AB)=16, Δν=270, 2H), 4.32 (m, 1H), 4.62 (m, 1H), 5.77 (broad s, 1H), 6.6(broad s, 1H), 7.0-7.9 (m, 13H).

MS (%): 552 (0.2, parent), 416 (1), 322 (5), 254 (20), 91 (100).

HRMS calc'd for C₃₀ H₃₁ N₄ O₃ F₃ : 552.2341. Found: 552.2288.

EXAMPLE 9N-tert-butyl-2-[3-(3-(3-thiomethylphenyl)ureido)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared in 78% yield.

¹ H-NMR (δ, CDCl₃): 1.22 (s, 9H), 2.35 (s, 3H), 2.58 (m, 1H), 2.97 (m,1H), 3.21 (AB quartet, J_(AB) =16, Δν=288, 2H), 4.18 (m, 1H), 4.40 (m,1H), 6.6-7.4 (m, 13H), 7.75 (broad s, 1H), 8.67 (broad s, 1H).

MS (%): 530 (0.7, parent), 322 (18), 261 (21), 165 (100), 132 (32).

HRMS calc'd for C₃₀ H₃₄ N₄ O₃ S: 530.2352. Found: 530.2332.

EXAMPLE 10tert-butyl-2-[3-(3-(3-tolyl)ureido)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoate

Prepared in 76% yield, mp 195° C.

¹ H-NMR (δ, CDCl₃): 1.4 (s, 9H), 2.29 (s, 3H), 2.72 (m, 1H), 3.19 (m,1H), 3.28 (AB quartet, J_(AB) =16, Δν=230, 2H), 4.22 (m, 1H), 4.7 (m,1H), 6.37 (broad s, 1H), 6.78-7.5 (m, 14H).

MS (%): 500 (18, parent+1), 484 (4), 444 (20), 426 (4), 337 (42), 311(100), 266 (20), 240 (30), 194 (34).

EXAMPLE 113-(3-Tolylureido)-7-phenyl-(N-2-adamantyl)carboxamidomethyl)-hexahydro-azepin-2-one

A. 7-Phenyl-hexahydroazepin-2-one

To a 250 ml round-bottomed flask equipped with N₂ inlet were added 7.33g (38.8 mmol) 2-phenylcyclohexanone oxime (Chem. Ber., 55, 3664 (1922))and 25 ml pyridine. The solution was cooled to 0° C., and 9.61 g (50.4mmol) p-toluenesulfonyl chloride was added. The reaction was allowed tostir overnight as the ice melted, and then poured into water. Excesschloride was skimmed off the surface, and the reaction mixture wasstirred at pH 4 for 3 hours. The precipitate was filtered, washed withwater, and dried to a solid, 4.65 g (55%), mp 135°-137° C. (J. Am. Chem.Soc., 82, 4671 (1960) gives mp 139°-141° C.).

B. 3-Bromo-7-phenyl-hexahydroazepin-2-one

To a 250 ml round-bottomed flask equipped with N₂ inlet were added 5.12g (24.6 mmol) phosphorus pentachloride and 45 ml methylene chloride. Tothe stirring mixture cooled to 0° C. was added dropwise over 20 minutes,a solution of 4.65 g (24.6 mmol) 7-phenyl-hexahydroazepin-2-one and 3.98ml (49.2 mmol) pyridine in 40 ml methylene chloride. To the stirringmixture at 0° C. was then added 9.25 g (24.6 mmol)phenyltrimethylammonium bromide tribromide. The reaction was thenallowed to warm to room temperature and stirred for 3 hours. It was thenevaporated, taken up in tetrahydrofuran, quenched with water,evaporated, and partitioned between water and methylene chloride. Theorganic layer was washed with water and saturated aqueous sodiumbisulfite, dried over sodium sulfate, and evaporated. The residue waschromatographed on silica gel with ethyl acetate/hexane as eluent toafford the product as an oil, 4.0 g (61%).

¹ H-NMR (δ, CDCl₃): 1.8-2.4 (m, 6H), 4.35 and 4.63 (multiplets, 1H),4.7-4.9 (m, 1H), 5.73 and 5.81 (broad singlets, 1H, NH), 7.2-0.74 (m,5H).

IR (cm.⁻¹,CHCl₃): 1670 (C═O).

MS (%): 267 (6,parent), 188 (39), 160 (70), 106 (100), 91 (43), 55 (59).

C. 3-Bromo-7-phenyl-(N-t-butoxycarbonylmethyl)hexahydroazepin-2-one

To a 100 ml three-necked round-bottomed flask equipped with N₂ inletwere added 0.30 g (6.07 mmol) sodium hydride, which was washed withhexane and suspended in 3 ml dry tetrahydrofuran. To the stirringmixture was added a solution of 1.55 g (5.78 mmol)3-bromo-7-phenylhexahydroazepin-2-one and 1.42 g (6.07 mmol) t-butyliodoacetate dropwise over 20 minutes. The reaction was stirred for 3hours at room temperature, quenched with saturated aqueous ammoniumchloride, and taken up in ethyl acetate. The organic layer was washedwith water and brine, dried over sodium sulfate, and evaporated. Theresidue was chromatographed on silica gel using ethyl acetate/hexane aseluent to afford the product as an oil, 1.65 g (75%).

¹ H-NMR (δ, CDCl₃): 1.40 and 1.42 (singlets, 9H, two diastereomers),1.8-2.4 (m, 6H), 3.6-3.9 (m, 2H), 4.56 and 4.95 (multiplets, 1H), 4.71and 5.16 (multiplets, 1H), 7.2-7.4 (m, 5H).

D. 3-Azido-7-phenyl-(N-butoxycarbonylmethyl)hexahydroazepin-2-one

To a 100 ml round-bottomed flask equipped with N₂ inlet were added 1.65g (4.32 mmol)3-bromo-7-phenyl-(N-t-butoxycarbonylmethyl)-hexahydroazepin-2-one, 4 mldimethylformamide, 0.34 g (5.18 mmol) sodium azide, and a drop of water.The mixture was heated at 80° C. for 36 hours, and then poured intowater and extracted into ethyl acetate. The organic layer was washedwith water and brine, dried over sodium sulfate and evaporated. Theresidue was chromatographed on silica gel with ethyl acetate/hexane aseluent to afford the product as an oil, 1.0 g (67%).

¹ H-NMR (δ, CDCl₃): 1.34 (s, 9H), 1.7-2.4 (m, 6H) (only one diastereomercould be accurately identified), 3.62 (AB quartet, J_(AB) =17, Δγ=193,2H), 4.38 (m, 1H), 4.77 (m, 1H), 7.2-7.4 (m, 5H).

IR (cm.⁻¹, KBr): 2106 (N₃) and 1739 and 1661 (C═O).

E. 3-Amino-7-phenyl-(N-t-butoxycarbonylmethyl)hexahydroazepin-2-one

The azide from step D above (6. 1.0 g, 2.91 mmol) was treated under 45lb/in² hydrogen in the presence of 200 mg 10% palladium-on-carbon in 30ml ethanol for 4.6 hours. The reaction was filtered through Celite® andevaporated to leave an oil, which was used directly in the followingstep.

¹ H-NMR (δ, CDCl₃): 1.6-2.4 (m, 6H), 3.63 (only one diastereomer couldbe accurately identified) (AB quartet, J_(AB) =17, Δγ=156, 2H), 4.02 (m,1H), 4.91 (m, 1H), 7.2-7.4 (m, 5H).

IR (cm.⁻¹, neat): 1741 and 1649 (C═O).

F.3-(3-Tolylureido)-7-phenyl-(N-t-butoxycarbonylmethyl)-hexahydroazepin-2-one

To a 100 ml round-bottomed flask equipped with N₂ inlet were added 1.28g (4.02 mmol)3-amino-7-phenyl-(N-t-butoxycarbonylmethyl)-hexahydroazepin-2-one, 5 ml1,2-dichlorethane and 0.57 ml (4.43 mmol) 3-tolylisocyanate. Thereaction was stirred for 3 hours at room temperature and chromatographedon silica gel, using ethyl acetate/hexane as eluent, to afford theproduct as an oil. The oil was crystallized from isopropyl ether to givea solid, mp 194°-196° C.

¹ H-NMR (δ, CDCl₃): 1.25 (s, 9H), 1.6-2.3 (m, 6H), 2.17 and 2.20(singlets, 3H, diastereomers), 3.56 (AB quartet, J_(AB) =17, Δγ=236,2H), 5.01 (d, J=11, 1H), 5.08 (m, 1H), 6.71 (d, J=7, 1H), 6.8-7.3 (m,9H), 7.87 (s, 1H).

IR (cm.⁻¹, KBr): 1743 and 1650 (C═O).

MS (%): 451 (14, parent), 159 (45), 117 (64), 107 (100), 91 (46), 57(41), 56 (48).

Anal. calc'd for C₂₆ H₃₃ N₃ O₄ : C, 69.16; H, 7.57; N, 9.31. Found: C,69.10; H, 7.75; N, 9.08.

G. 3-(3-Tolylureido)-7-phenyl-(N-carboxymethyl)hexahydroazepin-2-one

To a 100 ml round-bottomed flask equipped with N₂ inlet were added 1.5 g(3.32 mmol)3-(3-tolylureido)-7-phenyl-(N-t-butoxycarbonylmethyl)-hexahydroazepin-2-oneand 25 ml methylene chloride. The solution was cooled to 0° C. and 5 mltrifluoroacetic acid was added. The reaction was then stirred at 0° C.for 1.2 hours. The reaction was poured into water, extracted intomethylene chloride, and the organic layer was washed with water andbrine, dried over sodium sulfate, and evaporated. The residue wascrystallized from isopropyl ether to afford a solid, mp 121°-130° C.,1.1 g (84%).

¹ H-NMR (δ, CDCl₃): 1.4-2.2 (m, 6H), 2.22 and 2.24 (singlets, 3H (onefor each diastereomer)), 3.55 and 3.61 (AB quartet-1, J_(AB) =18, Δγ=138and AB quartet-2, J_(AB) =18, Δγ=348, 2H), 3.4-3.8 (m, 1H), 4.0-4.1 (m,1H), 6.6 and 6.78 (m, 2H), 7.07-7.4 (m, 9H).

IR (cm.⁻¹, KBr): 1740 and 1640 (C═O).

MS (%): 395 (9, parent), 159 (63), 133 (100), 98 (78).

HRMS calc'd for C₂₂ H₂₅ N₃ O₄ : 395.1769. Found: 395.1853.

H.3-(3-Tolylureido)-7-phenyl-(N-(N-2-adamantyl)carboxamidomethyl)-hexahydroazepin-2-one

To a 100 ml round-bottomed flask equipped with N₂ inlet were added 330mg (0.835 mmol)3-(3-tolylureido)-7-phenyl-(N-carboxymethyl)-hexahydroazepin-2-one, 5 ml1,2-dichloroethane, 0.25 g (1.7 mmol) 2-aminoadamantane, and 0.24 g(1.25 mmol) ethyl(dimethylaminopropyl)carbodiimide. The reaction wasstirred 3 days at room temperature and chromatographed on silica gelusing methanol/methylene chloride as eluent to afford an oil which wascrystallized from isopropyl ether to give a solid, 20 mg (4.5%), mp145°-153° C.

¹ H-NMR (δ, CDCl₃): 1.4-2.2 (m, 22H), 2.20 and 2.23 (singlets, 3H, foreach diastereomer), 3.6 (AB quartet, J_(AB) =14, Δγ=121 (for one set,other set obscured), 2H), 3.9 (m, 1H), 4.5-4.8 (m, 1H), 5.04 and 5.12multiplets, 1H), 6.08 and 6.42 (d, J=8, 1H), 6.7 and 7.0-7.4 (m, 9H),7.65 and 7.77 (m, 1H).

IR (cm.⁻¹, KBr): 1650 (C═O).

MS (%): 528 (6, parent), 193 (100), 171 (65).

HRMS calc'd for C₃₂ H₄₀ N₄ O₃ : 528.3100. Found: 528.3051.

Anal. calc'd for C₃₂ H₄₀ N₄ O₃ •0.5H₂ O: C, 71.48; H, 7.69; N, 10.42.Found: C, 71.61; H, 7.34; N, 10.27.

The title compounds of Examples 12-21 were prepared using a procedureanalogous to that of Example 11.

EXAMPLE 123-(3-Tolylureido)-7-benzyl-(N-t-butoxycarbonylmethyl)hexahydroazepin-2-one

Prepared in 79% yield, M.P. 75°-86° C.

¹ H-NMR (δ, CDCl₃): 1.3-2.1 (series of multiplets, 6H), 1.44 (s, 9H),2.29 (s, 3H), 2.7-3.2 (m, 2H), 4.05 (AB, J_(AB) =17, Δν=66, 2H), 4.2-4.3(m, 1H), 5.05 (m, 1H), 6.8-7.5 (m, 11H).

¹³ C-NMR (δ, CDCl₃): 21.5, 28.0, 30.4, 32.2, 39.7, 45.2, 52.3, 58.4,81.9, 117.1, 120.8, 127.0, 128.8, 128.9, 137.1, 155, 168.7, 175, (notall aromatic carbons assigned in this scan).

MS (%): 465 (9, parent), 374 (17), 185 (66), 170 (61), 107 (100), 91(64), 83 (43), 57 (58).

HRMS calc'd for C₂₆ H₄₀ N₃ O₄ : 465.2593. Found: 465.26576.

EXAMPLE 133-((3-Chlorophenyl)ureido)-7-cyclohexyl-(N-t-butoxycarbonylmethyl)-hexahydroazepin-2-one

Prepared in 87% yield, mp 75°-84° C.

¹ H-NMR (δ, CDCl₃): 1.3-2.1 (series of multiplets, 6H), 1.44 (s, 9H),2.7-3.2 (m, 2H), 4.06 (AB, J_(AB) =17, Δγ=62, 2H), 4.2-4.3 (m, 1H), 5.05(m, 1H), 6.9-7.6 (m, 11H).

MS (%): 485 (1, parent), 394 (22), 338 (23), 303 (34), (100), 170 (76),127 (90), 91 (73), 57 (74), 56 (80).

HRMS calc'd for C₂₆ H₃₇ N₃ O₄ F₃ : 485. 20929. Found: 485.20705.

EXAMPLE 143-((3-Chlorophenyl)ureido)-7-phenyl-(N-t-butoxycarbonylmethyl)-hexahydroazepin-2-one(more polar diastereomer)

Prepared in 55% yield, mp 201°-203° C.

¹ H-NMR (δ, CDCl₃): 1.38 (s, 9H), 1.6-2.4 (series of multiplets, 6H),4.05 (AB, J_(AB) =17, Δν=357, 2H), 4.5-4.7 (m, 2H), 6.6-7.8 (m, 11H).

IR (cm.⁻¹, KBr): 1719, 1680, 1625 (C═O).

MS (%): 471 (14, parent), 415 (47), 345 (52), 289 (100), 127 (51), 83(45), 55 (39).

Anal. calc'd for C₂₅ H₃₀ N₃ O₄ Cl: C, 63.62; H, 6.41; N, 8.90. Found: C,63.74; H, 6.49; N, 8.62.

EXAMPLE 153-(3-Tolylureido)-7-phenyl-(N-t-butoxycarbonylmethyl)hexahydroazepin-2-one(more polar diastereomer)

Prepared in 44% yield, mp 181°-183° C.

¹ H-NMR (δ, CDCl₃): 1.38 (s, 9H), 1.6-2.4 (series of multiplets, 6H),2.24 (s, 3H), 4.01 (AB, J_(AB) =17, Δν=381. 2H), 4.5-4.6 (m, 1H), 4.62(t, J=7, 1H), 6.57 (m, 1H), 6.76 (m, 1H), 7.0-7.5 (m, 9H).

IR (cm.⁻¹, KBr): 1721, 1680, 1636 (C═O).

Anal. calc'd for C₂₆ H₃₃ N₃ O₄ •0.25H₂ O: C 68.47, H 7.40, N 9.21.Found: C 68.71, H. 7.47, N 9.22.

EXAMPLE 163-((3-Methoxyphenyl)ureido)-7-phenyl-(N-t-butoxycarbonylmethyl)-hexahydroazepin-2-one(more polar diastereomer)

Prepared in 44% yield, mp 169°-170° C.

¹ H-NMR (δ, CDCl₃): 1.38 (s, 9H), 1.6-2.4 (series of multiplets, 6H),3.71 (s, 3H), 4.02 (AB, J_(AB) =17, Δν=375, 2H), 4.5-4.7 (m, 2H), 6.47(m, 1H), 6.50 (m, 1H), 6.81 (m, 1H), 7.0-7.6 (m, 8H).

IR (cm.⁻¹, KBr): 1727, 1628 (C═O).

Anal. calc'd for C₂₆ H₃₃ N₃ O₅ : C, 66.79; H, 7.11; N, 8.99. Found: C,66.59; H, 7.12; N, 8.92.

EXAMPLE 17 3-((3-Methoxyphenyl)ureido)-7-phenyl-(N-t-butoxycarbonylmethyl)-hexahydroazepin-2-one (less polardiastereomer)

Prepared in 39% yield, mp 180°-90° C.

¹ H-NMR (δ, CDCl₃): 1.27 (s, 9H), 1.6-2.4 (series of multiplets, 6H),3.69 (s, 3H), 3.57 (AB, J_(AB) =17, Δν=226, 2H), 5.01 (m, 1H), 5.08 (m,1H), 6.45 (m, 1H), 6.8 (m, 2H), 7.0-7.6 (m, 8H).

IR (cm.⁻¹, KBr): 1741, 1640, 1605 (C═O).

MS (%): 467 (11, parent), 159 (32), 123 (100), 117 (25).

Anal. calc'd for C₂₆ H₃₃ N₃ O₅ •0.5H₂ O: C, 65.53; H, 7.19; N, 8.82.Found: C, 65.44; H, 6.952; N, 8.84.

EXAMPLE 183-((3-Chlorophenyl)ureido)-7-phenyl-(N-t-butoxycarbonylmethyl)-hexahydroazepin-2-one(less polar diastereomer)

Prepared in 19% yield, as a foam.

¹ H-NMR (δ, CDCl₃): 1.26 (s, 9H), 1.6-2.4 (series of multiplets, 6H),3.51 (AB, J_(AB) =17, Δν=195, 2H), 5.00 (m, 1H), 5.08 (m, 1H), 6.8-7.4(m, 9H), 7.98 (broad s, 1H), 8.13 (broad s, 1H).

¹³ C-NMR (δ, CDCl₃): 27.1, 27.8, 31.1, 31.8, 46.8, 52.7, 60.5, 61.9,81.7, 117.2, 117.3., 117.4, 119.4, 122.5, 122.8, 128.7, 129.1, 129.79,129.82, 134.4, 134.5, 138.1, 140.1, 140.5, 153.0, 155.2, 168.5, 175.2.

IR (cm.⁻¹, KBr): 1741, 1629, 1598 (C═O).

MS (%): 471 (3, parent), 345 (20), 129 (35), 127 (100), 117 (22), 83(41).

HRMS calc'd for C₂₅ H₃₀ N₃ O₄ Cl: 471. 19411. Found: 471. 19455.

EXAMPLE 193-(3-Tolylureido)-7-phenyl-(N-t-adamantyl)carbonylmethyl)-hexahydroazepin-2-one

Prepared in 42% yield, mp 120°-130° C.

¹ H-NMR (δ, CDCl₃): 1.4-2.4 (series of multiplets, 20H), 2.23 (s, 3H),3.71 (AB, J_(AB) =17, Δν=213, 2H), 4.75 (m, 1H), 5.04 (m, 1H), 5.1 (m,1H), 6.75 (m, 2H), 7.0-7.6 (m, 9H).

IR (cm.⁻¹, KBr): 1750, 1650 (C═O).

MS (%): 529 (8, parent), 159 (46), 135 (49), 133 (47), 117 (31), 107(100), 85 (39), 83 (39).

Anal. calc'd for C₃₂ H₃₉ N₃ O₄ •0.5H₂ O: : C, 71.35; H, 7.48; N, 7.80.Found: C, 71.72; H, 7.33; N, 7.80.

EXAMPLE 203-(3-Tolylureido)-7-phenyl-(N-(1-adamantyl)carbonylmethyl)-hexahydroazepin-2-one

Prepared in 3% yield, as a foam.

¹ H-NMR (δ, CDCl₃): 1.4-2.4 (series of multiplets, 20H), 2.26 (s, 3H),3.57 (AB, J_(AB) =17, Δν=250, 2H), 5.02 (m, 1H), 5.1 (m, 1H), 6.7-6.8(m, 2H), 7.1-7.4 (m, 9H). IR (cm.⁻¹, KBr): 1745, 1650 (C═O).

MS (%): 529 (14, parent), 378 (60), 159 (78), 135 (100), 107 (60).

HRMS calc'd for C₃₂ H₃₉ N₃ O₄ : 529.29403. Found: 529.2902.

EXAMPLE 213-(3-Tolylureido)-7-phenyl-(N-(1-adamantyl)carboxamidomethyl)-hexahydroazepin-2-one

Prepared in 28% yield, mp 145°-154° C.

¹ H-NMR (δ, CDCl₃): 1.4-2.4 (series of multiplets, 20H), 2.245 (s, 3H),3.50 (AB, J_(AB) =16, Δν=174, 2H), 5.03 (m, 1H), 5.1 (m, 1H), 5.26 (s,1H), 6.7-6.8 (m, 2H), 7.1-7.7 (m, 9H).

IR (cm.⁻¹, KBr): 1645 (very broad) (C═O)

MS (%): 528 (<1, parent), 203 (36), 133 (100), 132 (30), 117 (44), 107(61), 104 (31).

Anal. calc'd for C₃₃ H₄₀ N₄ O₃ •0.5H₂ O: C, 71.48; H, 7.69; N, 10.42.Found: C, 71.37; H, 7.80; N, 10.29.

EXAMPLE 22

4-Phenyl-6-methyl-1,2,3,4-tetrahydronaphth-1-one

Prepared in analogy with a procedure in JACS, 69, 74 (1947) as shown inScheme 4:

A. 3-Carboethoxy-(4-phenyl, 4-(3-methylphenyl))-but-3-enoic acid

To a 250 mL round-bottomed flask equipped with condenser and N₂ inletwere added 100 mL t-butanol, 12.57 g (112 mmol) potassium t-butoxide, 20g (102 mmol) 3-methylbenzophenone, and 21.31 g (122 mmol) diethylsuccinate. The reaction was refluxed for 14 hours, cooled, and acidifiedwith HCl, then partitioned between water and ether. The organic layerwas washed with 1N aqueous sodium hydroxide solution, which was thenacidified and extracted into ether. The organic layer was dried andconcentrated to an orange oil which was used directly.

B. (4-Phenyl, 4-(3-methylphenyl))-but-3-enoic acid

The above oil was heated to reflux in a solution of 60 mL acetic acid,60 mL 48% hydrobromic acid, and 50 mL additional acetic acid forsolubility for 14 hours. The brown oil that separated on cooling wasisolated, dissolved in ethyl acetate, washed with water, then with 2%aqueous sodium hydroxide solution. The basic aqueous phase wasacidified, extracted into ethyl acetate, dried, and concentrated. Theproduct was a mixture of olefin isomers by NMR:

¹ H-NMR (δ, CDCl₃): 2.27 and 2.29 (s, 3H), 3.19 (m, 2H), 6.18 (t, J=7,1H), 6.8-7.4 (m, 9H).

C. (4-Phenyl, 4-(3-methylphenyl))-butanoic acid

The above oil (25.7 g) was hydrogenated at 30 p.s.i. hydrogen in ethylacetate with 1.25 g 10% palladium-on-carbon for 2 hours. Filtrationthrough Celite and concentration, followed by chromatography on silicagel using methanol/methylene chloride as eluant afforded an oil whichwas crystallized from heptane, 4.70 g (18%), M.P. 96°-100° C.

¹ H-NMR (δ, CDCl₃): 2.35 (s, 3H), 2.2-2.3 (m, 4H), 3.95 (t, J=7, 1H),7.0-7.4 (m, 9H).

¹³ C-NMR (δ, CDCl₃): 21.6, 30.3, 32.6, 50.4, 124.8, 126.5, 127.3, 127.9,128.5, 128.6, 138.2, 143.9, 144.2, 180.3.

IR (cm.⁻¹, KBr): 1720 (C═O).

MS (%): 254 (parent, 23), 182 (100), 165 (23), 32 (36), 28 (100).

Anal. calc'd for C₁₇ H₁₈ O₂ : C 80.28, H 7.13. Found: C 80.54, H 7.05.

D. 4-Phenyl-6-methyl-1,2,3,4-tetrahydronaphth-1-one:

To a 250 mL round-bottomed flask equipped with condenser and N₂ inletwere added 8.2 g (32.3 mmol) (4-phenyl,4-(3-methylphenyl))-butanoicacid, 54 mL toluene, and 4.6 g (38.64 mmol) thionyl chloride. Thereaction was refluxed for 1 hour, cooled, and concentrated. The oil wasdissolved in 15 mL carbon disulfide, and added dropwise to a slurry of29.98 g (225 mmol) aluminum chloride in 50 mL carbon disulfide which hadbeen cooled to 0° C. The reaction was allowed to stand 16 hours, pouredonto ice, and partitioned between water and ethyl acetate. The organicphase was washed with water, aqueous sodium bicarbonate solution, andwater, then dried and evaporated. The oil was chromatographed on silicagel using hexane/ethyl acetate as eluant to afford an oil, 4.03 g (53%).

¹ H-NMR (δ, CDCl₃): 2.28 (s, 3H), 2.2-2.7 (m, 4H), 4.24 (m, 1H), 6.8-7.4(m, 7H), 8.02 (d, J=7, 1H).

¹³ C-NMR (δ, CDCl₃): 21.8, 31.9, 36.4, 36.5, 45.2, 126.8, 128.1, 128.5,128.6, 129.9, 130.6, 143.8, 144.5, 146.2, 197.8.

IR (cm.⁻¹, KBr): 1680 (C═O).

MS (%): 236 (parent, 96), 208 (92), 194 (42), 166 (43).

E. 4-Phenyl-6-methyl-1,2,3,4-tetrahydronaphth-1-one oxime

To a 125 mL round-bottomed flask equipped with condenser and N₂ inletwere added 4.3 g (18.29 mmol)4-phenyl-6-methyl-1,2,3,4-tetrahydronaphth-1-one, 46 mL methanol, 2.95 g(29.26 mmol) triethylamine, and 2.02 g (29.26 mmol) hydroxylaminehydrochloride. The reaction was stirred at room temperature for 3 days,evaporated, partitioned between ethyl acetate and water, and the aqueouslayer extracted with fresh ethyl acetate. The combined organic layer wasdried over sodium sulfate and evaporated to an oil, 4.57 g (100%).

¹ H-NMR (d, CDCl₃): 2.1-2.3 (m, 2H), 2.28 (s, 3H), 2.8-3.0 (m, 2H), 4.17(m, 1H), 6.8-7.4 (m, 7H), 7.95 (d, J=7, 1H).

¹³ C-NMR (d, CDCl₃): 21.1, 21.4, 29.6, 45.0, 126.5, 128.0, 128.1, 128.5,129.2, 129.9, 139.7, 141.4, 144.0, 155.3.

IR (cm.⁻¹, KBr): 1610 (C═N).

MS (%): 251 (parent, 94), 234 (32), 156 (17), 91 (17).

HRMS: Calc'd. for C₁₇ H₁₇ NO: 251.1310. Found: 251.13022.

F. 5-phenyl-7-methyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one

To a 250 mL round-bottomed flask equipped with N₂ inlet were added 4.5 g(18.3 mmol) 4-phenyl-6-methyl-1,2,3,4-tetrahydronaphth-1-one oxime and59.45 g polyphosphoric acid. The mixture was heated in a 130° C. oilhath for 25 minutes, then poured onto ice and stirred until homogeneous.The mixture was extracted with ethyl acetate, and the organic layerwashed with water and brine, dried over sodium sulfate, and evaporated.The residue was chromatographed on silica gel using hexane/ethyl acetateas eluant to afford an oil, 2.20 g (49%), which could be crystallizedfrom methylene chloride and isopropyl ether to afford a solid, mp169°-173° C.

¹ H-NMR (δ, CDCl₃): 2.16 (s, 3H), 2.4-2.6 (m, 4H), 4.40 (m, 1H), 6.6 and7.0-7.4 (m, 8H), 9.15 (bs, 1H).

¹³ C-NMR (δ, CDCl₃): 21.1, 32.9, 33.9, 45.0, 121.9, 127.0, 127.9, 128.6,129.0, 129.1, 135.0, 135.2, 136.5, 141.2, 175.8.

IR (cm.⁻¹, KBr): 1680 (C═O).

MS (%): 252 (parent+1, 100), 196 (10), 147 (10), 135 (14), 119 (13), 103(12).

Anal. calc'd for C₁₇ H₁₇ NO: C 81.24, H 6.82, N 5.57. Found: C 81.04, H6.69, N 5.47.

The remainder of the synthesis was carried out as described in Example1:

G. 3-Bromo-5-phenyl-7-methyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one

M.P. 205°-211° C., 62% yield.

¹ H-NMR (δ, CDCl₃): 2.13 (s, 3H), 2.83 (m, 1H), 3.09 (m, 1H), 4.42 (m,1H), 4.62 (m, 1H), 6.6 and 7.0-7.4 (m, 8H), 8.99 (bs, 1H).

¹³ C-NMR (δ, CDCl₃): 21.1, 45.0, 46.1, 47.3, 122.5, 127.4, 128.3, 128.6,128.8, 128.9, 133.5, 133.6, 135.8, 136.4, 139.3, 169.3.

IR (cm.⁻¹, KBr): 1678 (C═O).

MS (%): 330/332 (parent, Br⁷⁹ /Br⁸¹, 100/98), 251 (26), 137 (32), 119(32), 85 (27).

Anal. calc'd for C₁₇ H₁₆ NOBr: C 61.83, H 4.88, N 4.24. Found: C 61.79,H 4.57, N 4.09.

H. N-t-Butyl2-[3-bromo-2-oxo-5-phenyl-7-methyl-2,3,4,5,-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

M.P. 129°-133° C., 93% yield.

¹ H NMR (δ, CDCl₃): 1.33 (s, 9H), 2.14 (s, 3H), 2.83 (m, 1H), 3.01 (m,1H), 4.3-4.5 (m, 2H), 4.59 (m, 1H), 4.66 (m, 1H), 6.14 (bs, 1H), 6.48(bs, 1H), 7.0-7.4 (m, 8H). ¹³ C-NMR (δ, CDCl₃): 21.2, 28.7, 43.9, 45.7,47.3, 51.5, 54.8, 123.0, 127.3, 128.3, 128.7, 128.8, 128.9, 129.0,137.4, 137.5, 138.4, 139.1, 167.1, 168.2.

IR (cm.⁻¹, KBr): 1662 (C═O).

MS (%): 443/445 (parent, Br⁷⁹ /Br⁸¹, 90/92), 370/372 (Br⁷⁹ /Br⁸¹,100/98), 290 (50), 262 (45), 134 (65).

Anal. calc'd for C₂₃ H₂₇ N₂ O₂ Br•1/3H₂ O: C 61.47, H 6.21, N 6.23.Found: C 61.20, H 6.12, N 5.96.

I.N-tert-butyl-2-[3-azido-2-oxo-5-phenyl-7-methyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Foam, mixture of diastereomers, 81% yield.

¹ H-NMR (δ, CDCl₃): 1.27, 1.32 (s's, 9H), 2.12, 2.37 (s's, 3H), 2.78 (m,1H), 2.95 (m, 1H), 2.98 (AB_(q), J_(AB) =15, Δν=279, part of 2H), 3.82,3.96, 4.06, and 4.64 (multiplets, 2H), 4.35 (s, rest of 2H), 6.17 (bs,1H), 6.45 (bs, 1H), 7.0-7.4 (m, 8H).

¹³ C-NMR (δ, CDCl₃): 21.0, 21.2, 28.6, 28.7, 35.5, 39.8, 41.9, 43.7,51.3, 51.5, 54.6, 58.3, 59.0, 60.4, 123.0, 125.6, 126.1, 126.5, 127.3,127.33, 127.4, 128.2, 128.3, 128.4, 128.5, 128.6, 128.65, 128.7, 128.8,128.9, 129.58, 129.64, 130.9, 137.2, 137.6, 137.7, 138.5, 139.4, 141.1,167.1, 167.9, 169.9, 170.4.

IR (cm.⁻¹, KBr): 2098 (N₃), 1660 (C═O).

MS (%): 406 (parent+1, 74), 380 (43), 347 (41), 333 9100), 249 (45), 234(62), 222 (77), 22o (74), 2o8 (79), 144 (51), 132 (41), 105 (47), 91(90).

HRMS calc'd for C₂₃ H₂₇ N₅ O₂ : 405.2165. Found: 405.21622.

J.N-tert-butyl-2-[3-amino-2-oxo-5-phenyl-7-methyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

M.P. 100°-110° C., mixture of diastereomers, 29% yield.

¹ H-NMR (δ, CDCl₃): 1.24, 1.31 (s's, 9H), 2.11, 2.35 (s's, 3H), 2.62(bs, 2H), 2.6-2.8 (m, 2H), 3.2-3.4 (m, 2H), 4.0-4.5 (m, 4H), 6.09 (bs,1H), 6.4 (bs, 1H), 7.0-7.4 (m, 8H).

IR (cm.⁻¹, KBr): 1660 (C═O).

MS (%): 379 (parent, 2), 336 (17), 235 916), 202 (22), 32 (35), 28(100).

HRMS calc'd. for C₂₃ H₂₉ N₂ O₂ : 379.2260. Found: 379.22848.

Anal. calc'd for C₂₃ H₂₉ N₃ O₂ •2/3H₂ O: C 70.56, H 7.81, N 10.73.Found: C 70.64, H 7.47, N 10.04 (-0.69).

K.N-tert-butyl-2-[3-(3-(3-tolyl)ureido)-2-oxo-5-phenyl-7-methyl-2,3,4,5-tetra-hydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared as a mixture of diastereomers, one of which precipitated fromthe reaction mixture (more polar); the other was purified bychromatography (less polar).

More polar isomer, M.P. 280°-283° C., 45.5% yield.

¹ H-NMR (δ, CDCl₃): 1.30 (s, 9H), 2.11 (s, 3H), 2.22 (s, 3H), 2.8-3.2(m, 2H), 3.90 (m, 1H), 4.34 (AB_(q), J_(AB) =16, Δν=59, 2H), 4.62 (m,1H), 6.4-6.8 (multiplets, 3H), 7.0-7.4 (m, 12H).

IR (cm.⁻¹, KBr): 1640 broad (C═O).

FAB MS (%): 513 (parent+1, 7), 380 (98), 307 (53), 155 (51), 119 (100).

HRMS calc'd for C₃₁ H₃₆ N₄ O₃ : 512.27541. Found: 512.27528.

Anal. calc'd for C₃₁ H₃₆ N₄ O₃ •2/3H₂ O: C 70.97, H 7.17, N 10.68.Found: C 70.80, H 6.71 (-0.46), N 10.39.

Less polar isomer, M.P. 130°-135° C., 42% yield.

¹ H-NMR (d, CDCl₃): 1.26 (s, 9H), 2.21 (s, 3H), 2.38 (s, 3H), 2.77 (m,1H), 3.01 (m, 1H), 3.22 (AB_(q), J_(AB) =16, Δν=287, 2H), 4.15 (m, 1H),4.60 (m, 1H), 5.89 (bs, 1H), 6.5-7.3 (m, 13H), 7.67 (bs, 1H).

¹³ C-NMR (d, CDCl₃): 21.0, 21.4, 28.6, 37.1, 44.4, 50.2, 51.6, 53.6,116.7, 123.4, 123.5, 126.3, 126.4, 128.3, 128.6, 129.4, 131.39, 131.43,137.7, 137.9, 138.5, 138.6, 139.1, 141.9, 155.4, 167.6, 173.0.

IR (cm.⁻¹, KBr): 1640 broad (C═O).

FAB MS (%): 513 (parent+1, 78), 440 (98), 380 (46), 305 (44), 251 (77),234 (93), 222 (67), 220 (45), 208 (100), 144 (44), 107 (54).

HRMS calc'd. for C₃₁ H₃₆ N₄ O₃ : 512.27541. Found: 512.28240.

Anal. calc'd for C₃₁ H₃₆ N₄ O₃ •1/2H₂ O: C 71.58, H 7.15, N 10.74.Found: C 71.55, H 7.10, N 10.33 (-0.41).

EXAMPLE 23N-tert-butyl-2-[3-(3-(3-chlorophenyl)ureido)-2-oxo-5-phenyl-7-methyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared as a mixture of diastereomers from the title compound ofExample 22J, one of which precipitated from the reaction mixture (morepolar); the other was purified by chromatography (less polar).

More polar isomer, M.P. 282°-285° C., 38% yield.

¹ H-NMR (δ, CDCl₃): 1.28 (s, 9H), 2.10 (s, 3H), 2.8-3.2 (m, 2H), 3.90(m, 1H), 4.32 (AB_(q), J_(AB) =16, Δν=52, 2H), 4.57 (m, 1H), 6.42 (bs,1H), 6.6-7.4 (m, 14H).

IR (cm.⁻¹, KBr): 1640 broad (C═O).

FAB MS (%): 533/535 (parent+1, Cl³⁵ /Cl³⁷, 9/4), 380 (52), 307/309(29/11), 155 (70), 135 (46), 119 (100), 103 (68).

Anal. calc'd for C₃₀ H₃₃ N₄ O₃ Cl•1/2H₂ O: C 66.47, H 6.32, N 10.34.Found: C 66.17, H 6.25, N 10.04.

Less polar isomer, M.P. 155°-165° C., 46% yield.

¹ H-NMR (δ, CDCl₃): 1.28 (s, 9H), 2.39 (s, 3H), 2.8-3.0 (m, 2H), 3.28(AB_(q), J_(AB) =16, Δν=281, 2H), 4.11 (m, 1H), 4.38 (m, 1H), 5.83 (bs,1H), 6.6-7.2 (m, 12H), 7.57 (bs, 1H), 7.98 (bs, 1H).

¹³ C-NMR (δ, CDCl₃): 21.0, 28.7, 36.8, 44.4, 50.4, 51.8, 53.2, 116.9,122.1, 126.3, 126.5, 128.3, 129.5, 131.5, 134.3, 137.7, 137.8, 137.9,138.4, 140.7, 141.9, 155.1, 167.4, 173.3.

IR (cm.⁻¹, KBr): 1640 broad (C═O).

FAB MS (%): 533/535 (parent+1, Cl³⁵ /Cl³⁷, 37/15), 460/462 (81/31), 380(33), 307 (61), 251 (61), 234 (100), 222 (62), 208 (99), 91 (51).

Anal. calc'd for C₃₀ H₃₃ N₄ O₃ Cl: C 67.598, H 6.24, N 10.51. Found: C67.50, H 6.18, N 10.14.

EXAMPLE 24N-tert-butyl-2-[3-(3-(3-methoxyphenyl)ureido)-2-oxo-5-phenyl-7-methyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared as a mixture of diastereomers from the tile compound of Example22J, one of which precipitated from the reaction mixture (more polar);the other was purified by chromatography (less polar).

More polar isomer, M.P. 283°-286° C., 47% yield.

¹ H-NMR (δ, CDCl₃): 1.31 (s, 9H), 2.11 (s, 3H), 2.8-3.2 (m, 2H), 3.7(singlets, 3H), 3.50 (m, 1H), 4.29 (AB_(q), J_(AB) =15, Δν=138, 2H),4.46 (m, 1H), 6.4-7.4 (multiplets, 15H).

IR (cm.⁻¹, KBr): 1640 broad (C═O).

FAB MS (%): 529 (parent+1, 7), 380 (100), 307 (92), 251 (47), 208 (42).

Anal. calc'd for C₃₁ H₃₆ N₄ O₄ •1/2H₂ O: C 69.25, H 6.94, N 10.42.Found: C 69.22, H 6.59, N 10.24.

Less polar isomer, M.P. 120°-125° C., yield 37%.

¹ H-NMR (δ, CDCl₃): 1.25 (s, 9H), 2.38 (s, 3H), 2.79 (m, 1H), 3.03 (m,1H), 3.25 (AB_(q), J_(AB) =16, Δνn=260, 2H), 3.68 (s, 3H), 4.17 (m, 1H),4.62 (m, 1H), 5.84 (bs, 1H), 6.5-7.3 (m, 13H), 7.80 (bs, 1H).

13C-NMR (δ, CDCl₃): 21.0, 28.6, 37.2, 44.3, 50.1, 51.6, 53.6, 55.1,104.7, 108.8, 111.5, 124.5, 126.3, 126.4, 128.3, 129.3, 129.4, 137.7,138.0, 138.5, 140.6, 141.9, 155.2, 160.1, 167.5, 172.9.

IR (cm.⁻¹, KBr): 1640 broad (C═O).

FAB MS (%): 529 (parent+1, 83), 456 (100), 380 (44), 307 (70), 251 (52),234 (67), 208 (65).

Anal. calc'd for C₃₁ H₃₆ N₄ O₄ •1/3H₂ O: C 68.87, H 6.96, N 10.36.Found: C 68.94, H 6.67, N 10.00.

EXAMPLE 25N-tert-butyl-2-[3-(3-(3-tolyl)ureido)-2-oxo-5-(3-chlorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

A. 4-Phenyl-6-chloro-1,2,3,4-tetrahydronaphth-1-one

Prepared in analogy with Example 22 above by treatment of(4-phenyl,4-(3-chlorophenyl))-butanoic acid (prepared in analogy with4-phenyl, 4-(3-methylphenyl)-butanoic acid as described above in Example22), with thionyl chloride in toluene followed by cyclization withaluminum chloride in carbon disulfide to afford the desired4-(3-chlorophenyl)-1,2,3,4-tetrahydronaphth-1-one and the isomericproduct 4-phenyl-6-chloro-1,2,3,4-tetrahydronaphth-1-one as aninseparable mixture in 53% yield, which was converted to the oximes andseparated.

B. 4-(3-Chlorophenyl)-1,2,3,4-tetrahydronaphth-1-one oxime

M.P. 129°-131° C., 28% yield.

¹ H-NMR (δ, CDCl₃): 1.56 (bs, 1H), 2.0-2.3 (m, 2H), 2.7-2.9 (m, 2H),4.18 (m, 1H), 6.8-7.4 and 8.0 (m, 8H).

¹³ C-NMR (δ, CDCl₃): 21.2, 29.3, 44.8, 124.2, 126.7, 127.2, 128.6,129.3, 129.8, 130.7, 134.5, 140.7, 146.0, 154.9.

IR (cm.⁻¹, KBr): 1598 (C═N).

MS (%): 271/273 (parent, Cl³⁵ /Cl³⁷, 100/35), 254 (42), 217 (24), 190(29).

Anal. calc'd for C₁₆ H₁₄ NOCl: C 70.72, H 5.19, N 5.15. Found: C 70.70,H 5.01, N 5.22.

C. 4-Phenyl-6-chloro-1,2,3,4-tetrahydronaphth-1-one oxime

Oil, 27% yield.

¹ H-NMR (δ, CDCl₃): 2.0-2.3 (m, 2H), 2.77 (t, J=7, 2H), 4.07 (m, 1H),6.8-7.3 and 7.86 (m, 8H).

(3-Chlorophenyl) compounds:

D. 5-(3-Chlorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one

Prepared as in Example 22, M.P. 174°-176° C., yield 51%.

Anal. calc'd for C₁₆ H₁₄ NOCl: C 70.72, H 5.19, N 5.15. Found: C 70.90,H 4.90, N 5.02.

E. 3-Bromo-5-(3-chlorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one

M.P. 154°-158° C., 51% yield.

Anal. calc'd for C₁₆ H₁₃ NOBrCl: C 54.81, H 3.74, N 3.99. Found: C 55.48(+0.67), H 3.46, N 3.87.

F. N-t-Butyl2-[3-bromo-2-oxo-5-(3-chlorophenyl)-2,3,4,5,-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

M.P. 148°-152° C. (from cyclohexane), 57% yield.

Anal. calc'd for C₂₂ H₂₄ N₂ O₂ BrCl•1/2 cyclohexane: C 59.36, H 5.98, N5.54. Found: C 59.26, H 6.16, N 5.54.

G.N-tert-butyl-2-[3-azido-2-oxo-5-(3-chlorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

M.P. 132°-135° C., 72.5% yield.

Anal. calc'd for C₂₂ H₂₄ N₅ O₅ Cl: C 62.04, H 5.68, N 16.44. Found: C62.12, H 5.56, N 16.51.

H.N-tert-butyl-2-[3-amino-2-oxo-5-(3-chlorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

The reduction was carried out with 1 equivalent of triphenylphosphineand water in tetrahydrofuran overnight at room temperature to give afoam in 95% yield.

HRMS calc'd for C₂₂ H₂₇ N₃ O₂ Cl: 400.1786. Found: 400.17876.

I.N-tert-butyl-2-[3-(3-(3-tolyl)ureido)-2-oxo-5-(3-chlorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared from a single diastereomer of the amino compound, which gave adiastereomer corresponding to the less polar isomer in Example 22K, M.P.251°-253° C., 85% yield.

¹ H-NMR (δ, CDCl₃, TFA): 1.33 (s, 9H), 2.33 (s, 3H), 2.79 (m, 1H), 2.96(m, 1H), 3.33 (AB_(q), J_(AB) =16, Δν=150, 2H), 4.22 (m, 1H), 4.58 (m,1H), 6.7-7.5 (m, 15H).

¹³ C-NMR (δ, CDCl₃, TFA): 20.7, 28.0, 36.3, 43.4, 50.5, 53.4, 53.5,121.4, 124.2, 124.8, 125.1, 125.9, 127.2, 128.6, 129.5, 129.8, 130.0,131.0, 134.1, 134.8, 137.2, 139.2, 140.6, 142.7, 158.2, 169.1, 173.6.

IR (cm.⁻¹, KBr): 1640 broad (C═O).

FAB MS (%): 533/535 (parent, Cl³⁵ /Cl³⁷, 32/13) 155, (46), 119 (100),103 (45).

Anal. calc'd for C₃₀ H₃₃ N₄ O₃ Cl.1/3H₂ O: C 66.84, H 6.29, N 10.39.Found: C 66.90, H 6.25, N 10.32.

EXAMPLE 26N-tert-butyl-2-[3-(3-(3-chlorophenyl)ureido)-2-oxo-5-(3-chlorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared from a single diastereomer of the amino compound, which gave adiastereomer corresponding to the less polar isomer in Example 22K, M.P.240°-243° C., 84% yield.

¹ H-NMR (δ, CDCl₃, TFA): 1.33 (s, 9H), 2.79 (m, 1H), 3.02 (m, 1H), 3.34(AB_(q), J_(AB) =16, Δν=143, 2H), 4.25 (m, 1H), 4.59 (m, 1H), 6.7-7.5(m, 15H).

¹³ C-NMR (δ, CDCl₃, TFA): 27.8, 36.6, 43.3, 44.0, 50.3, 53.4, 53.5,121.2, 123.4, 124.2, 124.7, 126.0, 126.8, 127.2, 129.9, 130.0, 130.7,131.1, 134.8, 135.5, 136.4, 137.2, 139.2, 142.7, 157.3, 169.1, 173.9.

IR (cm.⁻¹, KBr): 1640 broad (C═O).

FAB MS (%): 553/554/555/556/557 (parent+1, Cl³⁵ /Cl³⁷, 14/6/12/3/2), 309(16), 155 (60), 135 (30), 119 (100), 103 (42).

Anal. calc'd for C₂₉ H₃₀ N₄ O₃ Cl₂.1/3H₂ O: C 62.26, H 5.52, N 10.01.Found: C 62.32, H 5.38, N 9.77.

EXAMPLE 27N-tert-butyl-2-[3-(3-(3-methoxyphenyl)ureido)-2-oxo-5-(3-chlorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared from a single diastereomer of the amino compound, which gave adiastereomer corresponding to the less polar isomer in Example 22K, M.P.224°-227° C., 80% yield.

¹ H-NMR (δ, CDCl₃, TFA): 1.32 (s, 9H), 2.77 (m, 1H), 2.97 (m, 1H), 3.31(AB_(q), J_(AB) =16, Δν=157, 2H), 3.83 (s, 3H), 4.21 (m, 1H), 4.55 (m,1H), 6.7-7.5 (m, 15H).

¹³ C-NMR (δ, CDCl₃, TFA): 27.9, 36.4, 43.4, 50.4, 53.4, 55.5, 109.9,112.7, 116.4, 124.2, 124.8, 126.0, 127.2, 129.4, 129.9, 130.0, 130.7,131.1, 134.8, 136.1, 137.2, 139.3, 142.7, 157.7, 169.1, 173.8.

IR (cm.⁻¹, KBr): 1640 broad (C═O).

FAB MS (%): 549/551 (parent, Cl³⁵ /Cl³⁷, 45/17), 476 (23), 400 (22), 327(25), 155 (50), 135 (32), 119 (100), 103 (47).

Anal. calc'd for C₃₀ H₃₃ N₄ O₄ Cl: C 65.63, H 6.06, N 10.20. Found: C65.73, H 6.03, N 9.89.

EXAMPLE 28N-tert-butyl-2-[3-(3-(3-ethylphenyl)ureido)-2-oxo-5-(3-chlorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared from a single diastereomer of the amino compound, which gave adiastereomer corresponding to the less polar isomer in Example 22K, M.P.223°-228° C., 77% yield.

¹ H-NMR (δ, CDCl₃, TFA): 1.21 (t, J=7, 3H), 1.32 (s, 9H), 2.63 (q, J=7,2H), 2.77 (m, 1H), 2.98 (m, 1H), 3.31 (AB_(q), J_(AB) =16, Δν=174, 2H),4.23 (m, 1H), 4.58 (m, 1H), 6.7-7.5 (m, 15H).

¹³ C-NMR (δ, CDCl₃, TFA): 14.9, 27.9, 28.5, 36.4, 43.4, 50.4, 53.3,53.4, 121.4, 123.7, 124.2, 124.8, 126.0, 127.1, 127.2, 129.4, 129.9,130.0, 131.0, 134.5, 134.8, 137.2, 139.4, 142.7, 146.8, 158.1, 169.0,173.7.

IR (cm.⁻¹, KBr): 1640 broad (C═O).

FAB MS (%): 547/549 (parent, Cl³⁵ /Cl³⁷, 92/35) 474 (60), 400 (55), 327(72), 119 (100).

Anal. calc'd for C₃₁ H₃₅ N₄ O₃ Cl: C 68.06, H 6.45, N 10.24. Found: C67.98, H 6.35, N 10.05.

EXAMPLE 29

A. 5-phenyl-7-chloro-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one

Prepared from the title compound of Example 25C as in Example 25D, M.P.184°-186° C. 58% yield.

Anal. calc'd for C₁₆ H₁₄ NOCl: C 70.72, H 5.19, N 5.15. Found: C 71.00,H 4.86, N 5.07.

B. 3-Bromo-5-phenyl-7-chloro-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one

M.P. 220°-223° C. 56% yield.

Anal. calc'd for C₁₆ H₁₃ NOClBr: C 54.81, H 3.74, N 3.99. Found: C61.79, H 4.57, N 4.09.

C. N-t-Butyl2-[3-bromo-2-oxo-5-phenyl-7-chloro-2,3,4,5,-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

M.P. 125°-130° C. (from cyclohexane), 64% yield.

Anal. calc'd for C₂₂ H₂₄ N₂ O₂ ClBr.1/3 cyclohexane: C 58.61, H 5.74, N5.70. Found: C 58.72, H 5.50, N 5.58.

D.N-tert-butyl-2-[3-azido-2-oxo-5-phenyl-7-chloro-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

M.P. 167°-170° C., 38% yield.

Anal. calc'd for C₂₂ H₂₄ N₅ O₂ Cl•1/3H₂ O: C 61.18, H 5.76, N 16.21.Found: C 61.28, H 5.56, N 15.91.

E.N-tert-butyl-2-[3-amino-2-oxo-5-phenyl-7-chloro-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Foam, 65% yield.

HRMS calc'd for C₂₂ H₂₇ N₃ O₂ Cl: 400.1786. Found: 400.17952.

F.N-tert-butyl-2-[3-(3-(3-tolyl)ureido)-2-oxo-5-phenyl-7-chloro-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared from a single diastereomer of the amino compound, which gave adiastereomer corresponding to the less polar isomer in Example 22K, M.P.155°-160° C., 82% yield.

¹ H-NMR (δ, CDCl₃): 1.24 (s, 9H), 2.22 (s, 3H), 2.78 (m, 1H), 3.03 (m,1H), 3.18 (AB_(q), J_(AB) =16, Δν=279, 2H), 4.18 (m, 1H), 4.57 (m, 1H),5.76 (bs, 1H), 6.7-7.4 (m, 14H).

¹³ C-NMR (δ, CDCl₃): 21.5, 28.5, 36.9, 44.2, 50.1, 51.7, 53.5, 116.9,120.7, 123.8, 126.2, 126.7, 128.5, 128.7, 129.0, 130.5, 133.1, 138.8,139.7, 140.1, 141.0, 155.3, 167.2, 172.6.

IR (cm.⁻¹, KBr): 1640 broad (C═O).

FAB MS (%): 533/535 (parent, Cl³⁵ /Cl³⁷, 100/39), 460 (74), 400 (56),327 (72), 119 (68), 107 (72), 91 (67).

Anal. calc'd for C₃₀ H₃₃ N₄ O₃ Cl.1/3H₂ O: C 66.84, H 6.29, N 10.39.Found: C 66.87, H 6.19, N 10.13.

EXAMPLE 30N-tert-butyl-2-[3-(3-(3-chlorophenyl)ureido)-2-oxo-5-phenyl-7-chloro-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared from a single diastereomer of the amino compound, which gave adiastereomer corresponding to the less polar isomer in Example 22K, M.P.234°-236° C., 83% yield.

¹ H-NMR (δ, CDCl₃): 1.27 (s, 9H), 2.8-3.0 (m, 2H), 3.24 (AB_(q), J_(AB)=16, Δν=274, 2H), 4.21 (m, 1H), 4.55 (m, 1H), 5.76 (bs, 1H), 6.8-7.5 (m,13H), 7.92 (bs, 1H).

¹³ C-NMR (δ, CDCl₃): 28.7, 36.6, 44.3, 50.3, 52.0, 53.1, 53.5, 117.0,119.1, 122.4, 125.8, 126.2, 126.9, 128.5, 129.0, 129.6, 130.7, 133.2,134.3, 139.6, 140.0, 140.5, 140.9, 155.0, 167.0, 173.0.

IR (cm.⁻¹, KBr): 1640 broad (C═O). FAB MS (%): 553/554/555/556/557/558(parent, Cl³⁵ /Cl³⁷, 75/32/54/19/10), 400 (100), 327 (82), 254 (83), 228(73).

Anal. calc'd for C₂₉ H₃₀ N₄ O₃ Cl₂.1/3H₂ O: C 62.26, H 5.52, N 10.01.Found: C 62.49, H 5.40, N 9.70.

EXAMPLE 31N-tert-butyl-2-[3-(3-(3-tolyl)ureido)-2-oxo-5-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

A. 4-(4-Fluorophenyl)-1,2,3,4-tetrahydronaphth-1-one oxime

Prepared as in Example 22 above from the known4-(4-fluorophenyl)-1,2,3,4-tetrahydronaphth-1-one (see Koptyug, V. A.and Andreeva, T. P., Zh. Organich. Khim., 7, 2398-2403 (1971)) as shownin Scheme 5 in 93% yield, M.P. 154°-158° C. (from ethyl acetate/hexane).

¹ H-NMR (δ, CDCl₃): 2.0-2.3 (m, 2H), 2.84 (m, 2H), 4.13 (m, 1H), 6.9-7.3(m, 7H), 7.97 (m, 1H), 9.36 (bs, 1H).

¹³ C-NMR (δ, CDCl₃): 21.3, 29.5, 44.3, 115.2, 115.5, 124.1, 127.1,129.2, 129.6, 129.8, 129.9, 130.7, 139.4, 141.4, 155.1, 163.2.

IR (cm.⁻¹, KBr): 1602 (C═N).

MS (%): 255 (parent, 100), 238 (42), 183 (23).

HRMS calc'd for C₁₆ H₁₄ NOF: 255. 10595. Found: 255.10679.

B. 5-(4-Fluorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one

Prepared from the title compound of Example 31A as in Example 22F in 48%yield, M.P. 209-212° C. (from 2-propanol).

¹ H-NMR (δ, CDCl₃): 2.4-2.6 (m, 4H), 4.2 (m, 1H), 6.75 and 7.0-7.3 (m,8H), 8.41 (bs, 1H).

¹³ C-NMR (δ, CDCl₃): 32.7, 33.9, 44.3, 115.3, 115.6, 122.0, 125.7,127.4, 128.5, 130.2, 130.4, 136.6, 136.7, 137.3, 160.2, 160.4, 175.2.

IR (cm.⁻¹, KBr): 1680 (C═O).

MS (%): 255 (parent, 83), 213 (29), 200 (100), 198 (55), 183 (22).

Anal. calc'd for C₁₆ H₁₄ NOF: C 75.28, H 5.53, N 5.49. Found: C 75.20, H5.50, N 5.35.

The remainder of the synthesis was carried out as described in Example1:

C. 3-Bromo-5-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one

M.P. 170°-180° C. (from methylene chloride/hexane), 58% yield, mixtureof diastereomers.

¹ H-NMR (δ, CDCl₃): 2.8-3.2 (m, 2H), 4.50 (m, 1H), 4.65 (m, 1H), 6.7-7.4(m, 8H), 8.97 and 9.23 (singlets, 1H).

¹³ C-NMR (δ, CDCl₃): 43.8, 44.1, 44.3, 45.1, 46.2, 46.9, 115.4, 115.6,115.7, 115.9, 122.7, 126.6, 127.9, 128.1, 128.2, 129.1, 129.6, 129.7,129.8, 130.3, 130.5, 134.9, 135.0, 135.8, 136.2, 136.6, 160.4, 163.7,169.3, 170.2.

IR (cm.⁻¹, KBr): 1690 (C═O).

MS (%): 333/335 (parent, Br⁷⁹ /Br⁸¹, 46/50), 254 (100), 226 (100), 200(60), 198 (77), 109 (60).

HRMS calc'd for C₁₆ H₁₃ NOFBr: 333. 01466. Found: 333.01409.

D. N-t-Butyl2-[3-bromo-2-oxo-5-(4-fluorophenyl)-2,3,4,5,-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

M.P. 215°-220° C. (from cyclohexane), 59% yield.

¹ H-NMR (δ, CDCl₃): 1.32 (s, 9H), 2.8-3.0 (m, 2H), 4.2-4.6 (m, 3H), 4.77(m, 1H), 6.04 (bs, 1H), 6.6 and 7.0-7.4 (m, 8H).

¹³ C-NMR (δ, CDCl₃): 28.7, 43.1, 45.8, 47.0, 51.6, 54.6, 115.4, 115.7,123.2, 127.5, 127.6, 128.1, 130.3, 130.4, 130.5, 134.9, 135.0, 137.7,140.9, 163.6, 166.9, 167.9.

IR (cm.⁻¹, KBr): 1660 (C═O).

FAB MS (%): 447/449 (parent, Br⁷⁹ /Br⁸¹, 21/23), 374/376 (100/94),346/348 (48/46), 266 (93), 238 (44).

Anal. calc'd for C₂₂ H₂₄ N₂ O₂ BrF: C 59.07, H 5.41, N 6.26. Found: C59.05, H 5.15, N 6.20.

E.N-tert-butyl-2-[3-azido-2-oxo-5-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

M.P. 75°-85° C., mixture of diastereomers, 92% yield.

¹ H-NMR (δ, CDCl₃): 1.28, 1.32 (s's, 9H), 2.4-2.9 (m, 2H and part of a2H signal), 3.6, 3.77, 3.91, 4.12, 4.32, and 4.69 (multiplets for 2H andthe remaining 2H signal), 6.0 (broad singlets, 1H), 6.6 and 6.8-7.4 (m,8H).

¹³ C-NMR (δ, CDCl₃): 28.6, 35.9, 39.9, 41.1, 43.2, 51.6, 53.6, 54.5,58.2, 58.9, 115.1, 115.4, 115.7, 123.2, 125.9, 127.3, 127.5, 127.6,127.7, 127.8, 127.9, 128.0, 129.3, 129.5, 130.2, 130.3, 130.4, 135.1,137.5, 138.0, 140.2, 141.0, 166.9, 167.6, 169.8, 170.2.

IR (cm.⁻¹, KBr): 2100 (N₃), 1670 (C═O).

MS (%): 410 (parent+1, 55), 384 (35), 311 (19), 155 (50), 119 (100), 103(40).

HRMS calc'd for C₂₂ H₂₄ N₅ O₂ F: 409. 1914. Found: 409. 1903.

F.N-tert-butyl-2-[3-amino-2-oxo-5-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

The mixture of diastereomers was separated into an ethyl acetateinsoluble, M.P. 290°-295° C., 32% yield, isomer A and an isopropyl etherinsoluble, mp 215°-225° C., 32% yield, isomer B.

Isomer A:

¹ H-NMR (δ, CDCl₃): 1.26 (s, 9H), 2.48 (m, 1H), 2.7 (broad s, 2H), 3.03(m, 1H), 3.90 (m, 1H), 4.17 (AB_(q), J_(AB) =16, Dn=20, 2H), 4.87 (m,1H), 6.6 and 7.0-7.4 (m, 8H).

IR (cm.⁻¹, KBr): 1680 (C═O).

MS (%): 384 (parent+1, 100), 311 (44), 255 (19), 119 (20).

Isomer B:

¹ H-NMR (δ, CDCl₃): 1.26 (s, 9H), 2.5 (m, 1H), 3.0-3.4 (m, 2H), 2.61 (m,1H), 4.1-4.3 (m, 2H), 6.12 (broad s, 1H), 6.8-7.4 (m, 8H), 8.78 (broads, 2H).

¹³ C-NMR (d, CDCl₃): 22.8, 28.8, 43.2, 50.3, 51.8, 53.3, 115.1, 115.4,125.2, 128.1, 128.2, 129.4, 130.7, 136.6, 137.8, 140.1, 159.7, 162.9,167.5, 168.7.

IR (cm.⁻¹, KBr): 1680 (C═O).

MS (%): 383 (parent, 10), 340 (94), 267 (65), 261 (79), 255 (62), 239(81), 224 (65), 212 (100), 188 (86), 57 (80).

Anal. calc'd for C₂₂ H₂₆ N₃ O₂ F.H₂ CO₃ : C 62.01, H 6.33, N 9.43.Found: C 62.00, H 6.61, N 9.37.

G.N-tert-butyl-2-[3-(3-(3-tolyl)ureido)-2-oxo-5-(4-fluorophenyl)-2,3,4,,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared from each of the above isomers:

From isomer B, M.P. 302°-307° C. 69% yield.

¹ H-NMR (δ, CDCl₃, TFA): 1.34 (s, 9H), 2.34 (s, 3H), 2.85 (m, 1H), 3.03(m, 1H), 3.34 (AB_(q), J_(AB) =16, Δν=147, 2H), 4.27 (m, 1H), 4.62 (m,1H), 6.8-7.6 (m, 15H).

¹³ C-NMR (δ, CDCl₃, TFA): 20.4, 27.5, 36.6, 42.9, 50.6, 53.4, 53.6,115.2, 115.5, 121.5, 124.7, 125.3, 127.3, 127.4, 128.9, 129.5, 129.8,131.0, 133.7, 136.1, 137.6, 139.1, 140.8, 160.0, 169.2, 173.5.

IR (cm.⁻¹, KBr): 1650 broad (C═O).

FAB MS (%): 516 (parent, 17), 340 (100), 267 (70), 239 (58), 212 (46).

Anal. calc'd for C₃₀ H₃₃ N₄ O₃ F.1/3H₂ O: C 68.95, H 6.49, N 10.72.Found: C 68.89, H 6.31, N 10.59.

From isomer A, M.P. 310°-315° C., 55% yield.

¹ H-NMR (δ, CDCl₃, TFA): 1.35 (s, 9H), 2.32 (s, 3H), 2.93 (m, 2H),4.4-4.7 (m, 4H), 6.8 and 7.0-7.5 (m, 15H).

¹³ C-NMR (δ, CDCl₃, TFA): 20.5, 27.7, 40.9, 41.2, 51.5, 53.5, 53.8,115.5, 115.8, 121.7, 122.6, 125.4, 128.1, 128.9, 129.8, 129.9, 130.1,130.2, 133.6, 133.7, 133.8, 137.4, 138.3, 140.8, 158.3, 160.6, 163.9,169.0, 173.8.

IR (cm.⁻¹, KBr): 1650 broad (C═O).

FAB MS (%): 517 (parent+1, 2), 309 (15), 185 (20), 155 (58), (45), 119(100), 103 (57).

Anal. calc'd for C₃₀ H₃₃ N₄ O₃ F•H₂ CO₃ : C 65.81, H 6.34, N 10.07.Found: C 65.63, H 6.07, N 10.36.

EXAMPLE 32N-tert-butyl-2-[3-(3-(3-chlorophenyl)ureido)-2-oxo-5-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared from each of the above isomers in Example 31F:

From isomer B, M.P. 271°-273° C., 78% yield.

¹ H-NMR (δ, CDCl₃,TFA): 1.35 (s, 9H), 2.84 (m, 1H), 3.05 (m, 1H), 3.35(AB_(q), J_(AB) =16, Δν=139, 2H), 4.30 (m, 1H), 4.64 (m, 1H), 6.8-7.6(m, 15H).

¹³ C-NMR (δ, CDCl₃,TFA.sub.): 27.5, 36.8, 43.0, 50.5, 53.4, 53.8, 115.3,115.5, 121.5, 123.7, 124.7, 127.1, 127.3, 127.4, 129.5, 129.8, 130.7,131.0, 135.5, 136.0, 137.7, 139.1, 157.5, 160.0, 163.3, 169.3, 173.9.

IR (cm.⁻¹, KBr): 1650 broad (C═O).

FAB MS (%): 536 (parent, 5.5), 340 (76), 267 (65), 239 (100), 212 (76),127 (71).

Anal. calc'd for C₂₉ H₃₀ N₄ O₃ FCl•1/3H₂ O: C 64.14, H 5.69, N 10.32.Found: C 64.31, H 5.70, N 9.92.

From isomer A, M.P. 324°-328° C., 28% yield.

¹ H-NMR (δ, CD₃ SOCD₃): 1.20 (s, 9H), 2.03 (m, 1H), 2.75 (m, 1H), 4.18(m, 1H), 4.46 (AB_(q), J_(AB) =16, Δν=146), 2H), 5.16 (m, 1H), 6.5-7.7and 9.17 (m, 15H).

IR (cm.⁻¹, KBr): 1650 broad (C═O).

FAB MS (%): 537 (parent, 10), 309 (12), 233 (25), 155 (71), 135 (68),119 (100), 103 (83).

HRMS calc'd for C₂₉ H₃₀ N₄ O₃ FCl: 537.2062. Found: 537.2056.

Anal. calc'd for C₂₉ H₃₀ N₄ O₃ FCl•2H₂ CO₃ : C 56.32, H 5.18, N 8.48.Found: C 56.87 (+0.55), H 4.98, N 8.86.

EXAMPLE 33N-tert-butyl-2-[3-(3-(3-methoxyphenyl)ureido)-2-oxo-5-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared from each of the above isomers in Example 31F:

From isomer B, M.P. 275°-284° C., 60% yield.

¹ H-NMR (δ, CDCl₃, TFA): 1.33 (s, 9H), 2.82 (m, 1H), 3.01 (m, 1H), 3.34(AB_(q), J_(AB) =16, Δν=150, 2H), 3.87 (s, 3H), 4.26 (m, 1H), 4.61 (m,1H), 6.8-7.5 (m, 15H).

¹³ C-NMR (δ, CDCl₃, TFA): 27.6, 36.6, 43.0, 50.5, 53.3, 53.7, 55.6,115.2, 115.5, 124.7, 127.3, 127.4, 129.4, 129.8, 130.7, 131.0, 136.1,137.7, 139.1, 157.8, 160.0, 163.2, 169.2, 173.7.

IR (cm.⁻¹, KBr): 1650 broad (C═O).

MS (%): 532 (parent, 10), 340 (100), 267 (91), 239 (92), 212 (84).

Anal. calc'd for C₃₀ H₃₃ N₄ O₄ F•1/3H₂ O: C 66.90, H 6.30, N 10.40.Found: C 67.09, H 6.08, N 10.27.

From isomer A, M.P. 317°-320° C., 21% yield.

¹ H-NMR (δ, CD₃ SOCD₃): 1.20 (s, 9H), 2.16 (m, 1H), 2.91 (m, 1H), 3.66(s, 3H), 4.22 (m, 1H), 4.47 (AB_(q), J_(AB) =16, Δν=146, 2H), 5.10 (m,1H), 6.4-6.8, 7.0-7.5, 7.73, and 8.91 (m, 15H).

IR (cm.⁻¹, KBr): 1650 broad (C═O).

MS (%): 532 (parent, 5), 340 (68), 267 (77), 239 (86), (66), 188 (44),149 (100), 123 (72).

HRMS calc'd for C₃₀ H₃₄ N₄ O₄ F: 533.2556. Found: 533.2518.

Anal. calc'd for C₃₀ H₃₃ N₄ O₄ F•2H₂ CO₃ : C 57.14, H 5.54, N 8.33.Found: C 57.47, H 5.25, N 8.89 (+0.56).

EXAMPLE 34N-tert-butyl-2-[3-(3-(3-tolyl)ureido)-2-oxo-5-(2-fluorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

A. 4-(2-Fluorophenyl)-1,2,3,4-tetrahydronaphth-1-one oxime

Prepared as in Example 31 above from the known4-(2-fluorophenyl)-1,2,3,4-tetrahydronaphth-1-one (see Koptyug, V. A.and Andreeva, T. P., Zh. Organich. Khim., 7, 2398-2403 (1971)) in 90%yield, M.P. 118°-122° C. (from ethyl acetate/hexane).

Anal. calc'd for C₁₆ H₁₄ NOF: C 75.28, H 5.53, N 5.49. Found: C 74.84, H5.25, N 5.71.

B. 5-(2-Fluorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one

Prepared from the title compound of Example 34A as in Example 31 abovein 43% yield, M.P. 210°-213° C. (from 2-propanol).

Anal. calc'd for C₁₆ H₁₄ NOF: C 75.28, H 5.53, N 5.49. Found: C 75.30, H5.53, N 5.41.

The remainder of the synthesis was carried out as described in Example1:

C. 3-Bromo-5-(2-fluorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one

M.P. 208°-214° C. (from methylene chloride/hexane), 48% yield, mixtureof diastereomers.

Anal. calc'd for C₁₆ H₁₃ NOFBr: C 57.51, H 3.92, N 4.19. Found: C 57.60,H 3.66, N 4.35.

D. N-t-Butyl2-[3-bromo-2-oxo-5-(2-fluorophenyl)-2,3,4,5,-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

M.P. 85°-90° C. (from isopropyl ether/hexane), 100% yield.

HRMS calc'd for C₂₂ H₂₄ BrFN₂ O₂ : 446.0999. Found: 446.10136.

E.N-tert-butyl-2-[3-azido-2-oxo-5-(2-fluorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Mixture of diastereomers, 80% yield.

HRMS calc'd for C₂₂ H₂ N₅ O₂₄ F: 409.1914. Found: 409.19362.

F.N-tert-butyl-2-[3-amino-2-oxo-5-(2-fluorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

From the mixture of diastereomers, one isomer was isolated bycrystallization from ethyl acetate, M.P. 190°-195° C., in 22% yield.

Anal. calc'd for C₂₂ H₂₆ N₃ O₂ F: C 68.91, H 6.83, N 10.96. Found: C68.93, H 6.81, N 10.90.

G.N-tert-butyl-2-[3-(3-(3-tolyl)ureido)-2-oxo-5-(2-fluorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

One isomer was obtained from the title compound of example 34F, M.P.285°-300° C., 79% yield.

¹ H-NMR (δ, CDCl₃,TFA): 1.35 (s, 9H), 2.34 (s, 3H), 2.71 (m, 1H), 3.02(m, 1H), 3.44 (AB_(q), J_(AB) =17, Δν=230, 2H), 4.48 (m, 1H), 4.62 (m,1H), 6.8-7.6 (m, 15H).

¹³ C-NMR (d, CDCl₃): 20.5, 27.6, 37.0, 39.5, 50.8, 53.6, 53.7, 116.1,116.4, 121.4, 123.7, 124.0, 125.1, 126.2, 127.9, 128.7, 129.1, 129.2,129.3, 129.5, 129.8, 131.7, 136.1, 138.8, 140.7, 169.2, 173.7.

IR (cm.⁻¹, KBr): 1650 broad (C═O).

FAB MS (%): 517 (parent+1, 56), 311 (55), 255 (47), 212 (42), 119 (100).

Anal. calc'd for C₃₀ H₃₃ N₄ O₃ F: C 70.33, H 6.44, N 10.85. Found: C70.30, H 6.28, N 10.85.

EXAMPLE 35N-tert-butyl-2-[3-(3-(3-chlorophenyl)ureido)-2-oxo-5-(2-fluorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

One isomer was obtained, M.P. 270°-283° C. 82% yield.

¹ H-NMR (δ, CDCl₃, TFA): 1.36 (s, 9H), 2.72 (m, 1H), 3.04 (m, 1H), 3.55(AB_(q), J_(AB) =17, Δν=219, 2H), 4.50 (m, 1H), 4.64 (m, 1H), 6.8-7.6(m, 15H).

¹³ C-NMR (δ, CDCl₃,TFA): 27.6, 37.2, 39.6, 50.7, 53.6, 53.8, 116.2,116.5, 121.2, 123.4, 123.8, 124.0, 126.3, 126.3, 126.8, 128.0, 129.1,129.2, 129.3, 129.5, 130.6, 131.7, 135.5, 136.2, 138.9, 157.4, 169.3,174.1.

IR (cm.⁻¹, KBr): 1650 broad (C═O).

FAB MS (%): 537 (parent+1, 14), 311 (17), 238 (16), 195 (17), 155 (55),110 (100).

Anal. calc'd for C₂₉ H₃₀ N₄ O₃ FCl: C 64.86, H 5.63, N 10.43. Found: C64.90, H 5.38, N 10.20.

EXAMPLE 36N-tert-butyl-2-[3-(3-(3-methoxyphenyl)ureido)-2-oxo-5-(2-fluorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

One isomer was obtained from the title compound of Example 34F, mp265°-280° C., 83% yield.

¹ H-NMR (δ, CDCl₃, TFA): 1.35 (s, 9H), 2.74 (m, 1H), 3.02 (m, 1H), 3.61(AB_(q), J_(AB) =16, Δν=229, 2H), 3.87 (s, 3H), 4.52 (m, 1H), 4.64 (m,1H), 6.8-7.5 (m, 15H).

¹³ C-NMR (δ, CDCl₃): 27.6, 37.0, 39.5, 50.7, 53.5, 53.8, 55.6, 116.4,122.7, 123.7, 124.0, 126.2, 127.9, 129.1, 129.2, 129.3, 129.5, 130.7,131.7, 138.8, 157.7, 169.3, 174.0.

IR (cm.⁻¹, KBr): 1650 broad (C═O).

MS (%): 533 (parent+1,15), 311 (18), 195 (60), 155 (59), 135 (64), 110(100), 103 (85).

Anal. calc'd for C₃₀ H₃₃ N₄ O₄ F•1/4H₂ O: C 67.09, H 6.29, N 10.43.Found: C 67.12, H 6.02, N 10.42.

EXAMPLE 37N-tert-butyl-2-[3-(3-(3-tolyl)ureido)-2-oxo-5-(4-chlorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

A. 4-(4-Chlorophenyl)-1,2,3,4-tetrahydronaphth-1-one oxime

Prepared as in Example 31 above from the known4-(4-chlorophenyl)-1,2,3,4-tetrahydronaphth-1-one (see Koptyug, V. A.and Andreeva, T. P., Zh. Organich. Khim., 7, 2398-2403 (1971)) in 79%yield, M.P. 150°-154° C. (from ethyl acetate/hexane).

Anal. calc'd for C₁₆ H₁₄ NOCl: C 70.72, H 5.19, N 5.15. Found: C 70.70,H 5.37, N 5.08.

B. 5-(4-Chlorophenyl)-2.3,4,5-tetrahydro-1H-(1)benzazepin-2-one

Prepared from the title compound of Example 37A as in Example 31 abovein 31% yield, M.P. 209°-212° C. (from ethyl acetate/hexane).

Anal. calc'd for C₁₆ H₁₄ NOCl: C 70.72, H 5.19, N 5.15. Found: C 71.01,H 5.10, N 5.22.

The remainder of the synthesis was carried out as described in Example1:

C. 3-Bromo-5-(4-chlorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one

M.P. 194°-198° C. (from methylene chloride/hexane), 20% yield, mixtureof diastereomers.

Anal. calc'd for C₁₆ H₁₃ NOClBr•H₂ O: C 52.13, H 4.10, N 3.80. Found: C52.24, H 4.10 (+0.66), N 3.81.

D. N-t-Butyl2-[3-bromo-2-oxo-5-(4-chlorophenyl)-2,3,4,5,-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

M.P. 120°-130° C. (from cyclohexane), 75% yield.

Anal. calc'd for C₂₂ H₂₄ N₂ O₂ BrCl•2/3H₂ O: C 55.54, H 5.37, N 5.89.Found: C 55.45, H 4.82 (-0.55), N 5.93.

E.N-tert-butyl-2-[3-azido-2-oxo-5-(4-chlorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

M.P. 158°-168° C., mixture of diastereomers, 75% yield.

Anal. calc'd for C₂₂ H₂₄ N₅ O₂ Cl•1/3H₂ O: C 61.18, H 5.76, N 16.21.Found: C 61.03, H 5.59, N 15.81.

F.N-tert-butyl-2-[3-amino-2-oxo-5-(4-chlorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

The mixture of diastereomers was separated into an ethyl acetateinsoluble, 13% yield, isomer A and an ethyl acetate soluble foam, 82%yield, isomer B.

Isomer B:

HRMS calc'd for C₂₂ H₂₆ N₃ O₂ Cl: 399.1708. Found: 399.16959.

G.N-tert-butyl-2-[3-(3-(3-tolyl)ureido)-2-oxo-5-(4-chlorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

One isomer was obtained from isomer B above, M.P. 303°-310° C, 88%yield.

¹ H-NMR (δ, CDCl₃): 1.33 (s, 9H), 2.33 (s, 3H), 2.89 (m, 1H), 3.00 (m,1H), 3.35 (AB_(q), J_(AB) =16, Δν=159, 2H), 4.23 (m, 1H), 4.59 (m, 1H),6.8-7.6 (m, 15H).

¹³ C-NMR (δ, CDCl₃): 20.5, 27.7, 36.6, 43.1, 50.5, 53.5, 121.4, 124.7,125.2, 129.1, 128.7, 129.0, 129.4, 129.8, 129.9, 131.0, 133.1, 137.3,139.0, 139.2, 140.7, 158.1, 169.0, 173.5.

IR (cm.⁻¹, KBr): 1650 broad (C═O).

FAB MS (%): 356 (56), 261 (67), 188 (70), 133 (100), 57 (77), 28 (96).

Anal. calc'd for C₃₀ H₃₃ N₄ O₃ Cl: C 67.60, H 6.24, N 10.51. Found: C67.68, H 6.19, N 10.41.

EXAMPLE 38N-tert-butyl-2-[3-(3-(3-chlorophenyl)ureido)-2-oxo-5-(4-chlorophenyl)-2,3,4,5-tetra-hydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

One isomer was obtained from isomer B in Example 37F, M.P. 304°-307° C.,36% yield.

¹ H-NMR (δ, CDCl₃, TFA): 1.32 (s, 9H), 2.87 (m, 1H), 3.02 (m, 1H), 3.41(AB_(q), J_(AB) =16, Δν=151, 2H), 4.23 (m, 1H), 4.58 (m, 1H), 6.8-7.6(m, 15H).

¹³ C-NMR (δ, CDCl₃, TFA): 27.8, 43.1, 50.4, 53.5, 124.7, 127.2, 128.7,129.0, 129.4,129.9, 130.7, remaining carbons not visible in this scan.

IR (cm.⁻¹, KBr): 1650 broad (C═O).

FAB MS (%): 356 (48), 261 (43), 188 (44), 153 (100), 125 (45), 90 (52),57 (63), 28 (47).

Anal. calc'd for C₂₉ H₃₀ N₄ O₃ Cl₂ •1/2H₂ O: C 61.92, H 5.55, N 9.96.Found: C 61.95, H 5.31, N 9.90.

EXAMPLE 39N-tert-butyl-2-[3-(3-(3-methoxyphenyl)ureido)-2-oxo-5-(4-chlorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

One isomer was obtained from isomer B in Example 37F, M.P. 303°-307° C.,65% yield.

¹ H-NMR (δ, CDCl₃,TFA): 1.32 (s, 9H), 2.85 (m, 1H), 3.00 (m, 1H), 3.35(AB_(q), J_(AB) =16, Δν=161, 2H), 3.85 (s, 3H), 4.20 (m, 1H), 4.55 (m,1H), 6.8-7.5 (m, 15H).

¹³ C-NMR (δ, CDCl₃): 27.7, 36.6, 41.3, 43.1, 50.5, 53.4, 55.6, 122.7,124.7, 127.1, 128.7, 129.0, 129.4, 129.9, 130.7, 131.0, 133.1, 137.4,139.0, 139.2, 169.1, 173.9, 174.1.

IR (cm.⁻¹, KBr): 1650 broad (C═O).

MS (%): 548 (parent-1,2), 356 (32), 283 (37), 255 (34), 23 (100).

Anal. calc'd for C₃₀ H₃₃ N₄ O₄ Cl•1/3H₂ O: C 64.92, H 6.14, N 10.04.Found: C 65.19, H 5.93, N 9.99.

EXAMPLE 40N-tert-butyl-2-[3-(3-(3-tolyl)ureido)-2-oxo-5-(4-methylphenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

A. 4-[4-Methylphenyl)-1,2,3,4-tetrahydronaphth-1-one oxime

Prepared as in Example 31 above from the title compound of Example 40Afrom the known 4-(4-methylphenyl)-1,2,3,4-tetrahydronaphth-1-one (seeKoptyug, V. A. and Andreeva, T. P., Zh. Organich. Khim., 7, 2398-2403(1971)) in 94% yield, M.P. 97°-101° C. (from ethyl acetate/hexane).

Anal. calc'd for C₁₇ H₁₇ NO: C 81.24, H 6.82, N 5.57. Found: C 81.03, H6.63, N 5.57.

B. 5-[4-Methylphenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one

Prepared from the title compound of Example 40A as in Example 31 abovein 41% yield, M.P. 178°-181° C. (from ethyl acetate/hexane).

Anal. calc'd for C₁₇ H₁₇ NO: C 81.24, H 6.82, N 5.57. Found: C 80.80(-0.44), H 6.63, N 5.51.

The remainder of the synthesis was carried out as described in Example1:

C. 3-Bromo-5-(4-methylphenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one

M.P. 168°-176° C., 68% yield, mixture of diastereomers.

D. N-t-Butyl2-[3-bromo-2-oxo-5-(4-methylphenyl)-2,3,4,5,-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

M.P. 128°-138° C. (from hexane), 56% yield.

Anal. calc'd for C₂₃ H₂₇ N₂ O₂ Br: C 62.31, H 6.14, N 6.32. Found: C62.49, H 6.21, N 6.28.

E.N-tert-butyl-2-[3-azido-2-oxo-5-[4-methylphenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

M.P. 55°-65° C., mixture of diastereomers, 75% yield.

Anal. calc'd for C₂₃ H₂₇ N₅ O₂ •1/3H₂ O: C 67.13, H 6.78, N 17.02.Found: C 67.09, H 6.67, N 16.81.

F.N-tert-butyl-2-[3-amino-2-oxo-5-(4-methylphenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

The mixture of diastereomers was separated into an ethyl acetateinsoluble, mp 292°-295° C., 5.4% yield, isomer A and an isopropyl etherinsoluble, M.P. 150°-170° C., 12% yield, Isomer B.

Isomer A:

HRMS calc'd for C₂₃ H₂₉ N₃ O₂ : 379.2253. Found: 379.22664

Isomer B:

HRMS calc'd for C₂₃ H₂₉ N₃ O₂ : 379.2253. Found: 379.22455.

G.N-tert-butyl-2-[3-(3-(3-tolyl)ureido)-2-oxo-5-(4-methylphenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared from each of the above isomers of Example 40F:

From isomer B, M.P. 230°-238° C., 29% yield.

¹ H-NMR (δ, CDCl₃): 1.27 (s, 9H), 2.21 (s, 3H), 2.80 (m, 1H), 3.00 (m,1H), 3.21 (AB_(q), J_(AB) =16, Δν=296, 2H), 4.22 (m, 1H), 4.58 (m, 1H),6.07 (bs, 1H), 6.30 (bs, 1H), 6.8-7.4 (m, 12H), 7.64 (bs, 1H).

¹³ C-NMR (δ, CDCl₃): 21.4, 28.5, 37.1, 44.3, 50.1, 51.6, 53.7, 116.6,123.2, 123.5, 127.1, 127.7, 128.6, 128.8, 128.9, 129.0, 137.9, 138.2,138.7, 139.0, 141.1, 155.4, 167.9, 173.0.

IR (cm.⁻¹, KBr): 1650 broad (C═O).

FAB MS (%): 513 (parent+1, 82), 440 (92), 234 9100), 208 (96), 119 (85).

HRMS calc'd for C₃₁ H₃₆ N₄ O₃ : 512.27514. Found: 512.27474.

From isomer A, M.P. 298°-305° C., 68% yield.

¹ H-NMR (δ, CD₃ SOCD₃): 1.22 (s, 9H), 2.03 (m, 1H), 2.21 (s, 3H), 2.31(s, 3H), 2.82 (m, 1H), 4.45 (AB_(q), J_(AB) =16, Δν=135, 2H), 4.24 (m,1H), 4.99 (m, 1H), 6.5-7.3 (m, 13H), 7.66 (bs, 1H), 8.67 (bs, 1H).

¹³ C-NMR (δ, CD₃ SOCD₃): 21.2, 28.5, 41.2, 49.6, 50.3, 51.1, 114.7,118.1, 122.0, 123.0, 125.9, 126.4, 126.5, 127.0, 127.6, 128.4, 128.5,129.4, 137.6, 137.8, 139.0, 140.1, 140.5, 154.4, 167.0, 171.1.

IR (cm.⁻¹, KBr): 1650 broad (C═O).

FAB MS (%): 513 (parent+1, 10), 380 (100), 307 (56), 155 (46), 119 (98).

Anal. calc'd for C₃₁ H₃₆ N₄ O₃.5/4H₂ O: C 69.57, H 7.25, N 10.47. Found:C 69.55, H 7.05, N 10.42.

EXAMPLE 41N-tert-butyl-2-[3-(3-(3-chlorophenyl)ureido)-2-oxo-5-(4-methylphenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared from each of the above isomers in Example 40F:

From isomer B, M.P. 235°-238° C., 65% yield.

¹ H-NMR (δ, CDCl₃): 1.30 (s, 9H), 2.21 (s, 3H), 3.0 (m, 2H), 3.36(AB_(q), J_(AB) =16, Δν=291, 2H), 4.30 (m, 1H), 4.64 (m, 1H), 6.7-7.5(m, 13H), 7.57 (bs, 1H), 8.06 (bs, 1H).

¹³ C-NMR (δ, CDCl₃): 21.5, 28.7, 36.8, 44.5, 50.5, 51.9, 53.2, 116.9,119.0, 122.1, 123.4, 124.2, 126.1, 127.1, 127.2, 127.3, 127.8, 128.1,128.2, 129.0, 129.5, 130.9, 137.9, 138.3, 140.7, 141.1, 141.6, 155.2,167.4, 173.3.

IR (cm.⁻¹, KBr): 1650 broad (C═O).

FAB MS (%): 533 (parent+1, 35), 460 (67), 262 (37), 234 (100), 208 (85),105 (36).

Anal. calc'd for C₃₀ H₃₃ N₄ O₃ Cl: C 67.60, H 6.24, N 10.51. Found: C67.50, H 6.59, N 10.34.

From isomer A, M.P. 253°-263° C., 68% yield.

¹ H-NMR (δ, CD₃ SOCD₃): 1.21 (s, 9H), 2.03 (m, 1H), 2.31 (s, 3H), 2.75(m, 1H), 4.20 (m, 1H), 4.44 (AB_(q), J_(AB) =16, Δν=116), 2H), 4.96 (m,1H), 6.5-7.3 (m, 13H), 7.59 (bs, 1H), 8.17 (bs, 1H).

¹³ C-NMR (δ, CD₃ SOCD₃): 21.2, 28.4, 106.9, 115.5, 115.6, 120.7, 122.9,125.8, 126.4, 127.0, 127.1, 128.3, 129.4, 129.9, 133.3, 137.5, 139.2,140.3, 140.4, remaining carbons not visible in this scan.

IR (cm.⁻¹, KBr): 1650 broad (C═O).

FAB MS (%): 533 (parent+1, 12), 335 (15), 234 920), 169 (67), 155 (33),135 940), 119 (100), 103 (57).

HRMS calc'd for C₂₉ H₃₀ N₄ O₃ FCl: 532.2319. Found: 532.2312.

EXAMPLE 42N-tert-butyl-2-[3-(3-(3-methoxyphenyl)ureido)-2-oxo-5-(4-methylphenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared from isomer B from Example 40F, M.P. 233°-236° C., 60% yield.

¹ H-NMR (δ, CDCl₃,TFA): 1.27 (s, 9H), 2.20 (s, 3H), 2.85 (m, 1H), 3.10(m, 1H), 3.28 (AB_(q), J_(AB) =16, Δν=294, 2H), 3.68 (s, 3H), 4.24 (m,1H), 4.65 (m, 1H), 6.8-7.5 (m, 14H), 7.82 (bs, 1H).

¹³ C-NMR (δ, CDCl₃): 21.5, 28.6, 37.3, 44.4, 50.2, 51.7, 53.6, 55.1,104.9, 108.8, 111.6, 123.3, 124.7, 126.1, 127.1, 127.2, 127.7, 127.8,128.2, 128.9, 129.0, 129.4, 130.8, 137.9, 138.3, 140.6, 141.2, 155.2,160.2, 167.5, 173.0.

IR (cm.⁻¹, KBr): 1650 broad (C═O).

FAB MS (%): 529 (parent+1,50), 456 (68), 307 (50), 262 (50), 234 9100),208 (92).

Anal. calc'd for C₃₁ H₃₆ N₄ O₄ : C 70.43, H 6.86, N 10.60. Found: C70.23, H 7.22, N 10.36.

EXAMPLE 43N-tert-butyl-2-[3-(3-(3-ethylphenyl)ureido)-2-oxo-5-(4-methylphenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared from isomer B from Example 40F, M.P. 210°-214° C., 55% yield

¹ H-NMR (δ, CDCl₃): 114 (t, J=7, 3H), 1.26 (s, 9H), 2.20 (s, 3H), 2.52(q, J=7, 2H), 2.85 (m, 1H), 3.07 (m, 1H), 3.31 (AB_(q), J_(AB) =16,Δν=293, 2H), 4.23 (m, 1H), 4.64 (m, 1H), 5.90 (bs, 1H), 6.54 (bs, 1H),6.8-7.4 (m, 12H), 7.76 (bs, 1H).

¹³ C-NMR (δ, CDCl₃): 16.0, 20.9, 21.5, 28.6, 37.2, 44.4, 50.3, 51.6,53.6, 117.0, 119.4, 122.3, 123.3, 124.6, 126.2, 127.2, 127.7, 128.2,128.7, 129.0, 130.8, 137.9, 138.3, 139.2, 141.2, 141.8, 145.2, 155.4,167.6, 173.0.

IR (cm.⁻¹, KBr): 1650 broad (C═O)

FAB MS (%): 527 (parent+1, 40), 454 (47), 380 (45), 307 (60), 262 (53),234 (100), 208 (60).

Anal. calc'd for C₃₂ H₃₈ N₄ O₃ : C 72.98, H 7.27, N 10.64. Found: C72.97, H 7.74 (+0.47), N 10.39.

HRMS calc'd for C₃₂ H₃₈ N₄ O₃ : 526.2877. Found: 526.28695.

EXAMPLE 44N-tert-butyl-2-[3-(3-(3-tolyl)ureido)-2-oxo-5-(3,4-dichlorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

A. 4-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydronaphth-1-one oxime

Prepared as in Example 31A above from the known4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphth-1-one (see Quallich, G.J., Williams, M. T., Friedmann, R. C. J. Org. Chem., 55, 4971-4973(1991)) in 70% yield, M.P. 159°-162° C. (from methylenechloride/cyclohexane).

Anal. calc'd for C₁₆ H₁₃ NOCl₂ : C 62.76, H 4.28, N 4.57. Found: C62.41, H 4.04, N 4.44.

B. 5-(3,4-Dichlorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one

Prepared from the title compound of Example 44A as in Example 31B abovein 89% yield, M.P. 191°-194° C.

Anal. calc'd for C₁₆ H₁₃ NOCl₂ : C 62.76, H 4.28, N 4.57. Found: C62.56, H 4.14, N 4.59.

The remainder of the synthesis was carried out as described in Example1:

C.3-Bromo-5-(3,4-dichlorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one

M.P. 183°-188° C. (from ethyl acetate/hexane), 73% yield, mixture ofdiastereomers.

HRMS calc'd for C₁₆ H₁₂ NOBrCl₂ : 382.9477. Found: 382.9480.

D. N-t-Butyl2-[3-bromo-2-oxo-5-(3,4-dichlorophenyl)-2,3,4,5,-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

M.P. 85-95, 92% yield.

HRMS calc'd for C₂₂ H₂₃ N₂ O₂ BrCl₂ : 496.0315. Found: 496.03341.

E.N-tert-butyl-2-[3-azido-2-oxo-5-(3,4-dichlorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

M.P. 79°-99° C., mixture of diastereomers, 91% yield.

HRMS calc'd for C₂₂ H₂₃ N₅ O₂ Cl₂ : 459.1225. Found: 459.12421.

F.N-tert-butyl-2-[3-amino-2-oxo-5-(3,4-dichlorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared by reduction with triphenylphosphine in aqueous tetrahydrofuranas a mixture of diastereomers, which was separated into an isopropylether insoluble, M.P. 185°-190° C., 31% yield, isomer A and a chloroforminsoluble, M.P. 140°-150° C., 1.5% yield, isomer B. Isomer A:

Anal. calc'd for C₂₂ H₂₅ N₃ O₂ Cl₂ : C 60.83, H 5.80, N 9.67. Found: C60.91, H 5.71, N 9.46.

G.N-tert-butyl-2-(3-(3-(3-tolyl)ureido)-2-oxo-5-(3,4-dichlorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared from each of the above isomers from Example 44F:

From isomer B, M.P. 299°-301° C., 58% yield.

¹ H-NMR (δ, CD₃ SOCD₃): 1.23 (s, 9H), 2.21 (s, 3H), 2.92 (m, 1H), 3.4(m, 1H), 3.42 (AB_(q), J_(AB) =16, Δν=229, 2H), 4.35 (m, 1H), 4.58 (m,1H), 6.6-7.6 (m, 14H), 8.75 (bs, 1H).

¹³ C-NMR (δ, CDCl₃): 21.2, 28.5, 42.8, 48.7, 50.3, 51.9, 60.3, 72.3,114.8, 118.2, 122.0, 124.4, 126.9, 127.2, 128.4, 128.5, 128.6, 129.1,130.2, 130.8, 136.6, 137.8, 140.1, 141.7, 144.0, 154.1, 166.8, 170.3.

IR (cm.⁻¹, KBr): 1650 broad (C═O).

FAB MS (%): 566/568 (parent, Cl³⁵ Cl³⁷, 4/2) 390 (25), 289/291 (42/40),261 (50), 188 (60), 133 (100), 57 (65).

HRMS calc'd for C₃₀ H₃₂ N₄ O₃ Cl₂ : 566. 1845. Found: 566.1861.

From isomer A, M.P. 331°-334° C., 90% yield.

¹ H-NMR (δ, CD₃ SOCD₃): 1.20 (s, 9H), 2.10 (m, 1H), 2.20 (s, 3H), 2.82(m, 2H), 4.12 (m, 1H), 4.46 (AB_(q), J_(AB) =16, Δν=150, 2H), 5.04 (m,1H), 6.5-6.7 and 7.0-7.8 (m, 14H), 8.68 (bs, 1H).

IR (cm.⁻¹, KBr): 1650 broad (C═O)

FAB MS (%): 567 (parent, 1), 309 (6), 233 (17), 157 (100), 135 (23), 119(58), 103 (28).

Anal. calc'd for C₃₀ H₃₂ N₄ O₃ Cl₂ : C 63.49, H 5.68, N 9.87. Found: C63.82, H 5.60, N 9.60.

EXAMPLE 45N-tert-butyl-2-[3-(3-(3-chlorophenyl)ureido)-2-oxo-5-(3,4-dichlorophenyl)-2,3,-4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared from isomer A in Example 44F, M.P. 329°-332° C., 86% yield.

¹ H-NMR (δ, CD₃ SOCD₃): 1.20 (s, 9H), 2.08 (m, 1H), 2.80 (m, 1H), 4.20(m, 1H), 4.47 (AB_(q), J_(AB) =16, Δν=147), 2H), 5.10 (m, 1H), 6.5-7.8(m, 14H), 8.99 (bs, 1H).

¹³ C-NMR (δ, CD₃ SOCD₃): 28.9, 49.9, 50.8, 51.4, 56.1, 60.7, 72.7, 85.2,116.4, 117.4, 121.3, 123.7, 127.18, 122.22, 128.0, 129.6, 130.1, 130.7,131.18, 131.22, 133.6, 138.5, 140.7, 142.1, 142.3, 154.6, 167.5, 171.3.

IR (cm.⁻¹, KBr): 1650 broad (C═O).

FAB MS (%): 385 (35), 233 (18), 155 (56), 135 (35), 119 (100), 103 (44).

Anal. calc'd for C₂₉ H₂₉ N₄ O₃ Cl₃ : C 59.24, H 4.97, N 9.53. Found: C59.52, H 4.92, N 9.23.

EXAMPLE 46N-tert-butyl-2-[3-(3-(3-methoxyphenyl)ureido)-2-oxo-5-(3,4-dichlorophenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared from isomer A in Example 44F, M.P. 324°-327° C., 92% yield.

¹ H-NMR (δ, CD₃ SOCD₃): 1.20 (s, 9H), 2.08 (m, 1H), 2.83 (m, 1H), 3.67(s, 3H), 4.22 (m, 1H), 4.47 (AB_(q), J_(AB) =16, Δν=149, 2H), 5.14 (m,1H), 6.4-7.7 (m, 14H), 8.77 (bs, 1H).

¹³ C-NMR (δ, CD₃ SOCD₃): 28.9, 49.8, 50.8, 51.4, 55.3, 60.7, 72.7,103.7, 107.3, 110.3, 123.6, 123.7, 127.1, 127.2, 128.0, 129.6, 129.9,130.0, 131.1, 131.2, 131.7, 138.6, 40.8, 141.8, 142.4, 154.7, 160.1,167.5, 171.4.

IR (cm.⁻¹, KBr): 1650 broad (C═O)

MS (%): 583 (parent, 1), 456 921), 293 925), 279 (27), 233 939), 157(100), 156 (94), 154 (53), 135 (60), 119 (100), 103 (90).

Anal. calc'd for C₃₀ H₃₂ N₄ O₄ Cl₂ : C 61.75, H 5.53, N 9.60. Found: C61.81, H 5.35, N 9.37.

EXAMPLE 47N-tert-butyl-2-[3-(3-(3-tolyl)ureido)-2-oxo-5-phenyl-8-methyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

A. 8-Methyl-1-naphthol

Prepared from the known (J. Chem. Soc., C, (1966) 523)8-hydroxymethyl-1-naphthol by hydrogenolysis using 0.1 equiv. of 20%palladium hydroxide on carbon (Pearlmann's catalyst) in ethanol at 45psi hydrogen for 4 hours in quantitative yield, M.P. 56°-59° C.

B. 4-Phenyl-7-methyl-1,2,3,4-tetrahydronaphth-1-one and4-phenyl-8-methyl-1,2,3,4-tetrahydronaphth-1-one

Prepared from 8-methyl-1-naphthol using the procedure described above inExample 31 from Koptyug, V. A. and Andreeva, T. P., Zh. Organich. Khim.,7, 2398-2403 (1971) The products were separated by chromatography onsilica gel using hexane/ethyl acetate as eluant and crystallizedseparately from methanol. X-ray analysis of single crystals of bothcompounds, grown in methanol, established the structures of the twoisomers.

7-Methyl isomer, M.P. 72°-74° C.

¹ H-NMR (δ, CDCl₃): 2.2-2.8 (m, 4H), 2.36 (s, 3H), 4.25 (m, 1H), 6.8-7.4and 7.90 (m, 8H).

¹³ C-NMR (δ, CDCl₃): 21.0, 32.0, 36.8, 45.0, 126.7, 126.9, 127.2, 128.4,128.6, 129.5, 132.6, 134.6, 143.5, 143.9, 198.4.

IR (cm.⁻¹, KBr): 1681 (C═O).

MS (%): 236 (parent, 100), 194 (70), 165 (50).

Anal. calc'd for C₁₇ H₁₆ O: C 86.40, H 6.82. Found: C 86.39, H 6.76.

8-Methyl isomer, M.P. 60°-63° C.

¹ H-NMR (δ, CDCl₃): 2.2-2.7 (m, 4H), 2.68 (s, 3H), 4.28 (m, 1H), 6.8-7.3(m, 8H).

¹³ C-NMR (δ, CDCl₃): 23.4, 31.2, 38.1, 46.1, 126.6, 126.8, 127.8, 128.6,131.0, 131.6, 132.4, 141.2, 144.1, 147.3, 200.0.

IR (cm.⁻¹, KBr): 1680 (C═O).

MS (%): 236 (parent, 100), 208 (85), 165 (50). Anal. calc'd for C₁₇ H₁₆O: C 86.40, H 6.82. Found: C 86.77, H 6.66.

Preparation of5-phenyl-8-methyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one:

C. 4-Phenyl-7-methyl-1,2,3,4-tetrahydronaphth-1-one oxime

Prepared from 4-phenyl-7-methyl-1,2,3,4-tetrahydroaphth-1-one.

M.P. 143°-146° C., yield 72%.

Anal. calc'd for C₁₇ H₁₇ NO: C 81.24, H 6.82, N 5.57. Found: C 81.11, H7.02, N 5.51.

D. 5-phenyl-8-methyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one

M.P. 230°-234° C., yield 28.5%.

Anal. calc'd for C₁₇ H₁₇ NO: C 81.24, H 6.82, N 5.57. Found: C 81.25, H6.89, N 5.54.

The remainder of the synthesis was carried out as described in Example1:

E. 3-Bromo-5-phenyl-8-methyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one

M.P. 228°-232° C., 46% yield.

Anal. calc'd for C₁₇ H₁₆ NOBr•1/4H₂ O: C 61.00, H 4.97, N 4.18. Found: C61.07, H 5.01, N 4.38.

F. N-t-Butyl2-[3-bromo-2-oxo-5-phenyl-8-methyl-2,3,4,5,-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

M.P. 227°-230° C., 36% yield.

HRMS calc'd for C₂₃ H₂₇ N₂ O₂ Br: 442.1249. Found: 442.12321.

G.N-tert-butyl-2-[3-azido-2-oxo-5-phenyl-8-methyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

M.P. 112°-115° C., 56% yield as a single diasteromer.

Anal. calc'd for C₂₃ H₂₇ N₅ O₂ : C 68.13, H 6.71, N 17.27. Found: C68.40, H 6.82, N 17.12.

H.N-tert-butyl-2-[3-amino-2-oxo-5-phenyl-8-methyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide:

Prepared as a single diastersomer corresponding to isomer B of Example44F. M.P. 170°-180° C., 75% yield.

HRMS calc'd for C₂₃ H₂₉ N₃ O₂ : 379.2253. Found: 379.2267.

I.N-tert-butyl-2-[3-(3-(3-tolyl)ureido)-2-oxo-5-phenyl-8-methyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

M.P. 232°-238° C., 72% yield.

¹ H-NMR (δ, CDCl₃): 1.26 (s, 9H), 2.21 (s, 3H), 2.30 (s, 3H), 2.64 (m,1H), 2.92 (m, 1H), 3.12 (AB_(q), J_(AB) =16, Δν=283, 2H), 4.15 (m, 1H),4.50 (m, 1H), 6.10 (bs, 1H), 6.2-7.2 (m, 14H).

¹³ C-NMR (δ, CDCl₃): 21.0, 21.4, 28.5, 36.8, 43.8, 49.9, 51.5, 53.6,116.3, 120.0, 123.4, 125.2, 126.2, 126.3, 128.2, 128.3, 128.6, 130.5,135.1, 138.6, 139.0, 140.8, 141.9, 155.4 , 168.0, 173.0.

IR (cm.⁻¹, KBr): 1640 broad (C═O).

FAB MS (%): 512 (parent, 77), 440 (100), 307 (72), 208 (68).

Anal. calc'd for C₃₁ H₃₆ N₄ O₃ : C 72.63, H 7.08, N 10.93. Found: C72.29, H 6.85, N 10.78.

EXAMPLE 48N-tert-butyl-2-[3-(3-(3-chlorophenyl)ureido)-2-oxo-5-phenyl-8-methyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared from Example 47H, M.P. 155°-165° C., 68% yield.

¹ H-NMR (δ, CDCl₃): 1.29 (s, 9H), 2.33 (s, 3H), 2.8-3.0 (m, 2H), 3.32(AB_(q), J_(AB) =16, Δν=285, 2H), 4.20 (m, 1H), 4.56 (m, 1H), 6.6-7.3(m, 13H), 7.56 (bs, 1H), 8.00 (bs, 1H).

¹³ C-NMR (δ, CDCl₃): 21.1, 28.7, 36.8, 44.0, 50.5, 51.9, 53.1, 60.4,116.9, 118.9, 122.0, 124.8, 126.3, 126.4, 126.5, 128.3, 128.4, 129.5,130.7, 134.2, 135.0, 139.1, 140.7, 40.8, 142.0, 155.2, 167.4, 173.4.

IR (cm.⁻¹, KBr): 1640 broad (C═O).

FAB MS (%): 533/535 (parent+1, Cl³⁵ /Cl³⁷, 69/26), 460 (100), 307 (52),234 (60), 208 (70).

Anal. calc'd for C₃₀ H₃₃ N₄ O₃ Cl: C 67.60, H 6.24, N 10.51. Found: C67.27, H 6.06, N 10.23.

EXAMPLE 49 5-Phenyl-9-methyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one

Prepared as in Example 31 from4-phenyl-8-methyl-1,2,3,4-tetrahydronaphth-1-one.

A. 4-Phenyl-8-methyl-1,2,3,4-tetrahydronaphth-1-one oxime

M.P. 130°-136° C., 73% yield.

Anal. calc'd for C₁₇ H₁₇ NO: C 81.24, H 6.82, N 5.57 Found: C 81.19, H6.61, N 5.51.

B. 5-phenyl-9-methyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one

M.P. 154°-157° C., 81% yield.

Anal. calc'd for C₁₇ H₁₇ NO: C 81.24, H 6.82, N 5.57. Found: C 81.09, H6.52, N 5.45.

The remainder of the synthesis was carried out as described in Example1.

C. 3-Bromo-5-phenyl-9-methyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one

As a mixture of diastereomers, one of which had M.P. 240°243° C., 44%yield.

Anal. calc'd for C₁₇ H₁₆ NOBr: C 61.83, H 4.88, N 4.24. Found: C 61.79,H 4.57, N 4.09.

The remaining material, 26% yield, was obtained as a mixture ofdiastereomers, and was combined with the above diastereomer in the nextstep.

D. N-t-Butyl2-[3-bromo-2-oxo-5-phenyl-9-methyl-2,3,4,5,-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

The diastereomers were separated by chromatography on silica gel usinghexane/ethyl acetate as eluant, then crystallized from methylenechloride/hexane:

Isomer A, M.P. 199°-202° C., 15% yield.

Anal. calc'd for C₂₃ H₂₇ N₂ O₂ Br: C 62.31, H 6.14, N 6.32. Found: C62.60, H 5.87, N 6.12.

Isomer B, M.P. 227°-230° C., 63% yield.

Anal. calc'd for C₂₃ H₂₇ O₂ Br: C 62.31, H 6.14, N 6.32. Found: C 62.83(+0.52), H 6.48, N 6.22.

E.N-tert-butyl-2-[3-azido-2-oxo-5-phenyl-9-methyl-2,3,4,5-tetrahydro-1H-(1)-benzazepin-1-yl]ethanoicacid amide

Obtained as a mixture of diastereomers, which were separated bychromatography on silica gel using hexane/ethyl acetate as eluant.

Isomer A, oil, 18% yield.

HRMS calc'd for C₂₃ H₂₇ N₅ O₂ : 405.2159. Found: 405.21724.

Isomer B, M.P. 160°-164° C., 76% yield.

Anal. calc'd for C₂₃ H₂₇ N₅ O₂ : C 68.13, H 6.71, N 17.27. Found: C68.09, H 6.71, N 17.08.

F.N-tert-butyl-2-[3-amino-2-oxo-5-phenyl-9-methyl-2,3,4,5-tetrahydro-1H-(1)-benzazepin-1-yl]ethanoicacid amide

Each isomer from Example 49E was hydrogenated separately.

Isomer A, oil.

HRMS calc'd for C₂₃ H₂₇ N₅ O₂ : 380.2331. Found: 380.23462. Isomer B,oil, 13% yield.

HRMS calc'd for C₂₃ H₂₇ N₅ O₂ : 380.2331. Found: 380.23276.

G.N-tert-butyl-2-[3-(3-(3-tolyl)ureido)-2-oxo-5-phenyl-9-methyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared from isomer A above, M.P. 221°-223 ° C., 84% yield.

¹ H-NMR (δ, CDCl₃): 1.21 (s, 9H), 2.24 (s, 3H), 2.28 (s, 3H), 2.74(AB_(q), J_(AB) =16, Δν=135, 2H), 2.82 (m, 1H), 2.95 (m, 1H), 4.14 (m,1H), 4.51 (m, 1H), 6.54 (bs, 1H), 6.8-7.3 (m, 13H), 7.78 (bs, 1H).

¹³ C-NMR (δ, CDCl₃): 18.8, 21.5, 28.5, 35.8, 44.6, 50.0, 51.2, 53.5,55.2, 116.9, 120.6, 123.7, 126.3, 126.7, 128.4, 128.7, 128.8, 131.6,135.8, 138.8, 139.1, 139.3, 139.9, 141.3, 155.4, 168.0, 174.7.

IR (cm.⁻¹, KBr): 1640 broad (C═O).

FAB MS (%): 513 (parent+1, 27), 440 (100), 251 (37), 234 (65), 208 (50).

Anal. Calc'd for C₃₁ H₃₆ N₄ O₃ : C 72.63, H 7.08, N 10.93. Found: C72.89, H 7.02, N 10.90.

EXAMPLE 50N-tert-butyl-2-[3-(3-(3-methoxyphenyl)ureido)-2-oxo-5-phenyl-9-methyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared from isomer A in Example 49F, M.P. 162°-167° C., yield.

¹ H-NMR (δ, CDCl₃): 1.20 (s, 9H), 2.27 (s, 3H), 2.72 (AB_(q), J_(AB)=16, Δν=141, 2H), 2.75 (m, 1H), 2.92 (m, 1H), 3.71 (s, 3H), 4.2o (m,1H), 4.48 (m, 1a), 6.5-7.8 (m, 15H).

¹³ C-NMR (δ, CDCl₃): 18.8, 28.5, 36.0, 44.5, 50.0, 51.2, 53.4, 55.2,105.3, 109.2, 112.0, 126.3, 126.7, 128.4, 128.5, 128.7, 129.7, 131.6,135.8, 139.3, 139.8, 140.3, 141.2, 155.2, 160.3, 168.1, 174.6.

IR (cm.⁻¹, KBr): 1640 broad (C═O).

FAB MS (%): 529 (parent+1, 35), 456 (100), 307 (44), (62), 208 (54).

Anal. calc'd for C₃₁ H₃₆ N₄ O₄ •3/4H₂ O: C 68.68, H 6.97, N 10.33.Found: C 68.74, H 6.89, N 10.09.

EXAMPLE 51 N-tert-but1-2-3-3-3-chlorophenyl)ureido)-2-oxo-5-phenyl-9-methyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide:

Prepared from isomer A in Example 49F, M.P. 260°-262° C., 77% yield.

¹ H-NMR (δ, CDCl₃): 1.20 (s, 9H), 2.30 (s, 3H), 2.80 (AB_(q), J_(AB)=16, Δν=98, 2H), 2.8-3.0 (m, 2H), 4.26 (m, 1H), 4.48 (m, 1H), 6.17 (bs,1H), 6.8-7.3 (m, 12H), 7.56 (bs, 1H), 7.96 (m, 1H).

¹³ C-NMR (δ, CDCl₃): 18.9, 28.5, 35.6, 44.7, 50.2, 51.5, 54.4, 117.1,119.2, 122.4, 126.4, 126.7, 128.4, 128.5, 128.8, 129.7, 131.7, 134.4,135.6, 139.3, 139.8, 140.6, 141.3, 155.1, 167.4, 174.7.

IR (cm.⁻¹, KBr): 1640 broad (C═O).

FAB MS (%): 533/535 (parent, Cl³⁵ /Cl³⁷, 23/8), 460 (100), 408 (68), 234(85), 208 (75).

Anal. calc'd for C₃₁ H₃₆ N₄ O^(Cl:) C 67.60, H 6.24, N 10.51. Found: C67.59, H 6.25, N 10.18.

EXAMPLE 52N-tert-butyl-2-[3-(3-(3-ethylphenyl)ureido)-2-oxo-5-phenyl-9-methyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared from isomer A in Example 49F, M.P. 222°-224° C., 88% yield.

¹ H-NMR (δ, CDCl₃): 1.17 (t, J=7, 3H), 1.20 (s, 9H), 2.28 (s, 3H), 2.55(q, J=7, 2H), 2.72 (AB_(q), J_(AB) =16, Δν=136, 2H), 2.76 (m, 1H), 2.92(m, 1H), 4.20 (m, 1H), 4.50 (m, 1H), 6.60 (bs, 1H), 6.8-7.3 (m, 14H).

¹³ C-NMR (δ, CDCl₃): 15.6, 18.8, 28.5, 28.9, 36.0, 44.5, 50.0, 51.2,55.4, 117.4, 119.8, 122.8, 126.3, 126.7, 128.4, 128.5, 128.7, 128.9,131.6, 135.8, 138.9, 139.3, 139.9, 141.2, 145.4, 155.3, 168.1, 174.6.

IR (cm.⁻¹, KBr): 1640 broad (C═O).

FAB MS (%): 527 (parent+1, 37), 454 (100), 307 (45), 234 (54), 208 (47).

Anal. calc'd for C₃₂ H₃₈ N₄ O₃ : C 72.98, H 7.27, N 10.64. Found: C72.77, H 7.24, N 10.27.

EXAMPLE 53 N-Methyl,tert-butyl-2-[3-(3-(3-tolyl)ureido)-2-oxo-5-(phenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared from N-methyl,N-tert-butyl-2-[3-amino-2-oxo-5-(phenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide as in Example 1, M.P. 140°-150° C., 83% yield.

¹ H-NMR (δ, CDCl₃): 1.30 (s, 9H), 2.19 (s, 3H), 2.31 (s, 3H), 2.88 (m,1H), 3.15 (m, 1H), 3.32 (AB_(q), J_(AB) =16, Δν=297, 2H), 4.20 (m, 1H),4.68 (m, 1H), 6.6-7.4 (m, 14H), 7.72 (bs, 1H).

¹³ C-NMR (δ, CDCl₃): 21.5, 28.1, 30.5, 38.1, 44.4, 49.8, 53.0, 57.4,116.9, 120.7, 123.0, 124.9, 126.0, 126.6, 127.5, 128.2, 128.3, 128.6,128.7, 130.4, 138.3, 138.9, 139.5, 141.4, 142.7, 154.9, 166.9, 172.3.

IR (cm.⁻¹, KBr): 1650 broad (C═O).

FAB MS (%): 513 (parent+1, 40), 426 (100), 293 (42), 220 (46), 194 (50).

Anal. calc'd for C₃₁ H₃₆ N₄ O₃ : C 72.63, H 7.08, N 10.93. Found: C72.83, H 7.16, N 10.84.

EXAMPLE 54 N-Methyl,tert-butyl-2-[3-(3-(3-chlorophenyl)ureido)-2-oxo-5-(phenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared from N-methyl,N-tert-butyl-2-[3-amino-2-oxo-5-(phenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide as in Example 1, M.P. 155°-162° C., 97% yield.

¹ H-NMR (δ, CDCl₃): 1.32 (s, 9H), 2.50 (s, 3H), 2.84 (m, 1H), 3.02 (m,1H), 3.40 (AB_(q), J_(AB) =16, Δν=288), 2H),4.26 (m, 1H), 4.62 (m, 1H),6.8-7.6 (m, 14H), 7.96 (bs, 1H).

¹³ C-NMR (δ, CDCl₃): 28.2, 30.7, 38.0, 44.5, 49.6, 53.1, 57.5, 117.4,118.9, 121.5, 124.7, 126.2, 126.6, 127.5, 128.2, 128.8, 129.3, 130.5,133.8, 138.7, 141.1, 141.3, 142.6, 154.6, 167.0, 172.8.

IR (cm.⁻¹, KBr): 1650 broad (C═O).

FAB MS (%): 533 (parent+1, 14), 446 (80), 293 (54), 237 (52), 220 (98),194 (100).

Anal. calc'd for C₃₀ H₃₃ N₄ O₃ Cl: C 67.60, H 6.24, N 10.51. Found: C67.78, H 6.26, N 10.40.

EXAMPLE 55 N-benzyl,tert-butyl-2-(3-(3-(3-tolyl)ureido)-2-oxo-5-(phenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared from N-benzyl,N-tert-butyl-2-[3-amino-2-oxo-5-(phenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide as in Example 1, M.P. 226°-230° C., 63.5% yield.

¹ H-NMR (δ, CDCl₃): 1.33 (s, 9H), 2.18 (s, 3H), 2.88 (m, 1H), 3.10 (m,1H), 3.18 (AB_(q), J_(AB) =16, Δν=243, 2H), 4.0-4.3 (m, 3H), 4.75 (m,1H), 6.6-7.6 (m, 14H), 8.75 (bs, 1H).

¹³ C-NMR (δ, CDCl₃): 21.5, 28.5, 37.9, 44.4, 47.7, 49.5, 53.2, 58.3,116.8, 120.4, 122.9, 125.5, 125.9, 126.0, 126.3, 127.0, 127.1, 127.6,127.9, 128.0, 128.3, 128.7, 128.8, 128.9, 130.2, 138.2, 139.2, 139.4,141.5, 142.3, 155.0, 168.3, 172.8.

IR (cm.⁻¹, KBr): 1650 broad (C═O).

FAB MS (%): 589 (parent+1, 10), 426 (54), 293 (41), 220 (40), 91 (100).

Anal. calc'd for C₃₇ H₄₀ N₄ O₃ : C 75.48, H 6.85, N 9.52. Found: C75.09, H 6.88, N 9.30.

EXAMPLE 56 N-Benzyl,tert-butyl-2-[3-(3-(3-chlorophenyl)ureido)-2-oxo-5-(phenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared from N-benzyl,N-tert-butyl-2-[3-amino-2-oxo-5-(phenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide as in Example 1, M.P. 239°-243° C., 68% yield.

¹ H-NMR (δ, CDCl₃): 1.32 (s, 9H), 2.98 (m, 2H), 3.22 (AB_(q), J_(AB)=16, δν=204), 2H), 4.27 (AB_(q), J_(AB) =17, Δν=61), 2H), 4.31 (m, 1H),5.26 (m, 1H), 6.8-7.6 (m, 14H), 7.79 (bs, 1H).

¹³ C-NMR (δ, CDCl₃): 28.6, 37.7, 44.4, 47.7, 49.4, 53.5, 58.5, 117.1,121.5, 125.5, 125.7, 126.1, 126.2, 126.3, 127.0, 127.6, 127.7, 127.9,128.7, 128.8, 128.9, 129.2, 130.2, 133.8, 138.1, 139.2, 140.9, 141.4,142.2, 154.8, 168.1, 173.5.

IR (cm.⁻¹, KBr): 1650 broad (C═O).

FAB MS (%): 609 (parent+1, 8), 446 (56), 293 (37), 220 (57), 194 (44),91 (100).

Anal. calc'd for C₃₆ H₃₇ N₄ O₃ Cl: C 70.98, H 6.12, N 9.20. Found: C70.68, H 6.30, N 8.95.

EXAMPLE 57 N-Benzyl,tert-butyl-2-[3-(3-(3-methoxyphenyl)ureido]-2-oxo-5-(phenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared from N-benzyl,N-tert-butyl-2-[3-amino-2-oxo-5-(phenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide as in Example 1, M.P. 222°-226° C., 62% yield.

¹ H-NMR (δ, CDCl₃): 1.33 (s, 9H), 2.90 (m, 1H), 3.09 (m, 1H), 3.17(AB_(q), J_(AB) =16, Δν=236, 2H), 3.65 (S, 3H), 4.1-4.3 (m, 3H), 4.77(m, 1H), 6.4-7.4 (m, 14H), 7.55 (bs, 1H).

¹³ C-NMR (δ, CDCl₃): 28.5, 37.9, 44.4, 47.7, 49.4, 53.3, 55.1, 58.3,104.2, 109.0, 111.6, 125.5, 125.8, 126.2, 126.9, 127.0, 127.6, 127.7,127.9, 128.0, 128.6 128.8, 129.1, 130.2, 138.3, 139.2, 140.8, 141.4,142.3, 154.8, 159.9, 168.2, 172.8.

IR (cm.⁻¹, KBr): 1650 broad (C═O)

MS (%): 605 (parent+1, 10, 442 (72), 293 (55), 220 (59), 194 (56), 91(100).

Anal. calc'd for C₃₇ H₄₀ N₄ O₄ •1.5H₂ O: C 70.34, H 6.86, N 8.87. Found:C 70.40, H 6.48, N 8.65.

EXAMPLE 58 N-tert-Amyl2-[3-(3-(3-tolyl)ureido)-2-oxo-5-(phenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared from N-tert-amyl2-[3-amino-2-oxo-5-(phenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide as in Example 1, M.P. 226°-229° C., 70% yield.

¹ H-NMR (δ, CDCl₃): 0.73 (t, J=7, 3H), 1.21 (s, 9H), 1.63 (q, J=7, 2H),2.23 (s, 3H), 2.88 (m, 1H), 3.04 (m, 1H), 3.26 (AB_(q), J_(AB) =16,Δν=282, 2H), 4.11 (m, 1H), 4.60 (m, 1H), 5.80 (bs, 1H), 6.5-7.4 (m,13H), 7.70 (bs, 1H).

¹³ C-NMR (δ, CDCl₃): 8.3, 21.4, 26.2, 32.8, 37.1, 44.4, 50.2, 53.6,54.4, 116.7, 120.4, 120.5, 123.5, 124.8, 126.3, 126.5, 127.7, 128.3,128.6, 129.0, 130.8, 138.3, 138.7, 139.1, 141.2, 141.8, 155.4, 167.5,173.0.

IR (cm.⁻¹, KBr): 1650 broad (C═O)

FAB MS (%): 513 (parent+1, 65), 426 (50), 119 (100), 103 (48).

Anal. calc'd for C₃₁ H₃₆ N₄ O₃ : C 72.63, H 7.08, N 10.93. Found: C72.57, H 6.78, N 10.67.

EXAMPLE 59 N-tert-Amyl2-[3-(3-(3-chlorophenyl)ureido)-2-oxo-5-(phenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared from N-tert-amyl2-[3-amino-2-oxo-5-(phenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide as in Example 1, M.P. 219°-222° C., 73% yield.

¹ H-NMR (δ, CDCl₃): 0.74 (t, J=7, 3H), 1.23 (s, 9H), 1.64 (q, J=7, 2H),2.94 (m, 1H), 3.01 (m, 1H), 3.32 (AB_(q), J_(AB) =16, Δν=274, 2H), 4.15(m, 1H), 4.59 (m, 1H), 5.73 (bs, 1H), 6.5-7.4 (m, 12H), 7.57 (bs, 1H),7.97 (bs, 1H).

¹³ C-NMR (δ, CDCl₃): 8.4, 26.2, 32.9, 36.9, 44.5, 50.4, 53.2, 54.7,117.0, 118.9, 119.0, 122.1, 124.3, 124.4, 126.3, 126.4, 126.6, 127.8,128.3, 129.1, 129.5, 130.9, 134.3, 138.2, 140.7, 141.1, 141.8, 155.1,167.2, 173.2.

IR (cm,⁻¹, KBr): 1650 broad (C═O)

FAB MS (%): 533/535 (parent+1, Cl³⁵ /Cl³⁷ 34/13), 446 (75), 293 (60),220 (86), 194 (100).

Anal. calc'd for C₃₀ H₃₃ N₄ O₃ Cl: C 67.60, H 6.24, N 10.26. Found: C67.25, H 6.06, N 10.27.

EXAMPLE 60Trans-1-(t-Butylacetamido)-3-(3-tolylureido)-5,7-diphenylhexahydroazepin-2-one

A. 2,4-Diphenylcyclohexanone

Prepared in analogy with a method in Hussey, A. S. and Herr, R. R., J.Org. Chem., 24, 843, (1959). To a 500 mL round-bottomed flask equippedwith N₂ inlet were added 37 g (0.212 mol) of 4-phenylcyclohexanone and80 mL carbon tetrachloride. To the stirring solution was added dropwiseover 30 minutes a solution of 20.5 mL (0.255 mol) sulfuryl chloride in10 mL carbon tetrachloride. The reaction was stirred 14 hours at roomtemperature and poured into saturated aqueous sodium bicarbonatesolution. The organic layer was separated, washed again with saturatedaqueous sodium bicarbonate solution, dried over sodium sulfate, andevaporated to a yellow oil, 34.8 g (78%) which was used directly in thenext step.

¹ H-NMR (δ, CDCl₃): (mixture of diastereomers) 1.9-3.6 (series ofmultiplets, 7H), 4.7 and 5.3 (multiplets, 1H), 7.2-7.4 (m, 5H).

IR (cm.⁻¹, KBr): 1735 (C═O)

MS (%): 208/210 (parent, Cl³⁵ /Cl³⁷, 36/12), 145 (49), 117 (88), 115(83), 104 (100), 101 (88), 91 (82), 55 (67).

The oil was dissolved in 400 mL benzene and added dropwise over 40minutes to 83 mL (250 mmol) of a 3.0M solution of phenylmagnesiumbromide in ether, cooling so the temperature did not rise above 10° C.The reaction was then allowed to warm and heated to reflux for 14 hours.It was then cooled, quenched with aqueous ammonium chloride solution,then washed with water and brine, dried over sodium sulfate, andevaporated. The yield was 53.9 g (approximately theoretical), and thecrude oil was used directly in the next step.

¹ H-NMR (δ, CDCl₃): (mixture of diastereomers) 1.9-3.3 (series ofmultiplets, 7H), 3.9 (m, 1H), 7.1-7.6 (m, 10H).

B. 2,4-Diphenylcyclohexanone oxime

The above oil was dissolved in 200 mL methanol, and a solution of 18.6 g(0.267 mol) hydroxylamine hydrochloride and 37.2 mL (0.267 mol)triethylamine in 100 mL methanol added. The solution was decanted offthe oily precipitate which separated and stirred at room temperature for1.5 hours. The white precipitate was filtered and dried to give 13.6 g(31%) of a white solid, mp 214°-215° C.

C. 5,7-diphenylhexahydroazepin-2-one

To a 250 mL round-bottomed flask equipped with N₂ inlet were added 8.52g (32.15 mmol) 2,4-diphenylcyclohexanone oxime and 110 mL pyridine. Oncethe solid had dissolved, the solution was cooled to 0° C., and 12.3 g(64.3 mmol) p-toluenesulfonyl chloride was added. The reaction wasallowed to stir for 16 hours while the ice bath melted and the reactionwarmed to room temperature. It was then poured into 300 mL 3N HCl,extracted into ethyl acetate, and the organic layer washed withadditional HCl and brine, dried over sodium sulfate, and evaporated. Theresidue was chromatographed on silica gel using methanol/methylenechloride as eluant to afford 2.4 g (28%) of an oil which wascrystallized from isopropanol to give mp 171°-173.5° C.

¹ H-NMR (δ, CDCl₃): 2.0 (m, 1H), 2.1 (m, 3H), 2.75 (m, 2H), 2.95 (m,1H), 4.60 (m, 1H), 5.78 (bs, NH, 1H), 7.1-7.5 (m, 10H).

¹³ C-NMR (δ, CDCl₃): 30.3, 36.3, 45.3, 48.6, 58.1, 126.3, 126.6, 128.4,128.7, 129.2, 142.1, 146.1, 176.5.

IR (cm.⁻¹, KBr): 1662 (C═O).

MS (%): 265 (parent, 82), 266 (85), 160 (47), 106 (100), 104 (87).

Anal. calc'd for C₁₈ H₁₉ NO: C 81.48, H 7.21, N 5.27. Found C 81.32, H7.41, N 5.28.

D. 3-Bromo-5,7-diphenylhexahydroazepin-2-one

To a 250 mL round-bottomed flask equipped with addition funnel and N₂inlet were added 1.51 g (7.27 mmol) phosphorus pentachloride and 25 mLdry methylene chloride. The mixture was cooled with stirring to 0° C.,and a solution of 1.93 g (7.27 mmol) 5,7-diphenylhexahydroazepin-2-oneand 1.18 mL (14.5 mmol) pyridine in 50 mL methylene chloride was addeddropwise over 20 minutes. The reaction was stirred 5 minutes at 0° C.,then 0.82 mL (16.0 mmol) bromine in 5 mL methylene chloride was addeddropwise over 5 minutes. The reaction was stirred 5 minutes at 0° C.,then 1.8 hours at room temperature. The reaction was evaporated, takenup in 40 mL of 1:1 tetrahydrofuran:water, and stirred for 1.2 hours. Thereaction was then poured into water and extracted into ethyl acetate.The organic layer was washed with aqueous sodium bisulfite solution andbrine, dried over sodium sulfate, and evaporated to an oil.

The oil was taken up in 20 mL methylene chloride and 20 mL ethanol, andhydrogenated under 42 psi hydrogen in the presence of 0.30 g 10%palladium-on-carbon and 3 drops of quinoline for 1 hour. Tlc showedmostly desired monobromo product at R_(f) =0.4, with a little dibromoprecursor at R_(f) =0.7 and starting lactam at R_(f) =0.15, in 1/1-ethylacetate/hexane. The reaction was filtered through Celite with ethanoland methylene chloride, evaporated, and chromatographed on silica gelusing 2/1-hexane/ethyl acetate as eluant to afford 2.06 g (82%) of afoam M.P. 70°-78° C.

¹ H-NMR (δ, CDCl₃): (mixture of diastereomers) 1.9-2.7 (m, 4H), 3.12 and3.52 (multiplets, 1H), 4.52 and 4.76 (multiplets, 1H), 5.01 (m, 1H),5.79 and 5.89 (broad singlets, 1H, NH), 7.1-7.4 (m, 10H).

¹³ C-NMR (δ, CDCl₃): 42.4, 44.0, 48.0, 50.5, 57.6, 126.3, 126.6, 126.9,127.1, 128.7, 128.9, 129.3, 129.4, 169.6.

IR (cm.⁻¹, KBr): 1667 (C═O).

MS (%): 343/345 (11/10, parent for Br^(79/81)), 236 (32), 117 (32), 106(100), 91 (39), 55 (31).

Anal. calc'd for C₁₈ H₁₈ NOBr: C 62.80, H 5.27, N 4.07. Found: C 62.86,H 5.26, N 3.98.

E. 1-(t-Butylacetamido)-3-bromo-5,7-diphenylhexahydroazepin-2-one

To a 100 mL 3-necked round-bottomed flask equipped with addition funneland N₂ inlet were added 0.32 g (6.59 mmol) sodium hydride, which wasthen washed with hexane, and 4 mL dry tetrahydrofuran. To the stirringsuspension was added a solution of 2.06 g (5.99 mmol)3-bromo-5,7-diphenylhexahydroazepin-2-one and 1.59 g (6.59mmol) t-butyliodoacetamide. The reaction was stirred at room temperature for 60hours, quenched with ammonium chloride solution, then poured into water,extracted twice into ethyl acetate, washed with brine, dried over sodiumsulfate, and evaporated. The residue was chromatographed on silica gelusing 2/1-hexane/ethyl acetate as eluant to afford 1.585 g (58%) of anoil, R_(f) =0.4 (1/1-hexane ethyl acetate).

¹ H-NMR (δ, CDCl₃): (mixture of diastereomers) 1.22 and 1.25 (singlets,9H, ratio 35/65), 2.0-2.7 (m, 4H), 3.08 and 3.21 (multiplets, 1H),3.5-3.9 (m, 2H), 5.01 and 5.4-5.7 (m, 2H), 7.1-7.4 (m, 10H).

¹³ C-NMR (δ, CDCl₃): 14.2, 26.9, 28.7, 40.6, 43.9, 51.1, 60.3, 61.7,126.8, 127.0, 128.2, 128.4, 128.7, 128.9, 139.5, 144.6, 167.5, 170.0.

IR (cm.⁻¹, KBr): 1675 and 1632 (C═O).

MS (%): 377 (parent-Br, 39), 304 (42), 219 (21), 144 (25), 118 (31), 117(33), 115 (42), 104 (21), 91 (100), 57 (50), 55 (34).

F. 1-(t-Butylacetamido)-3-azido-5,7-diphenylhexahydroazepin-2-one

To a 100 mL round-bottomed flask equipped with N₂ inlet were added 1.58g (3.46 mmol)1-(t-butylacetamido)-3-bromo-5,7-diphenylhexahydroazepin-2-one, 5 mL drydimethylformamide, and 0.27 g (4.15 mmol) sodium azide. The reaction washeated at 80° C. for 3.5 days, cooled, poured into water, and extractedinto ethyl acetate. The organic layer was washed with water and brine,dried over sodium sulfate, and evaporated. The residue waschromatographed on silica gel using 40% ethyl acetate in hexane aseluant to afford 1.09 g (75%) of an oil, which was found to be an 8/3mixture of diastereomers, R_(f) =0.4-0.5 in 1/1-ethyl acetate/hexane.

1H-NMR (δ, CDCl₃): 1.21 and 1.31 (singlets, 9H), 2.17 and 2.58(multiplets, 4H), 3.05 and 3.32 (multiplets, 1H), 3.57 (AB_(q), J_(AB)=16, Δν=213 for one isomer of the 2 proton signal CH₂ CONHt-butyl),4.4-5.0 (multiplets, 2H), 5.68 and 6.17 (singlets, 1H, NH), 7.0-7.3 (m,10H).

IR (cm.⁻¹, KBr): 2105 (N₃), 1647 (C═O).

MS (%): 377 (parent-N₃, <1), 319 (parent-(CONHt-butyl), 4), 235 (21),146 (43), 115 (47), 104 (73), 103 (40), 91 (100), 84 (32), 57 (46).

G. 1-(t-Butylacetamido)-3-amino-5,7-diphenylhexahydroazepin-2-one

A solution of 1.09 g (2.60 mmol)1-(t-butylacetamido)-3-azido-5,7-diphenylhexahydroazepin-2-one in 30 mLethanol and 15 mL methylene chloride was hydrogenated at 42 psi in thepresence of 0.40 g 10% palladium-on-carbon for 36 hours. The reactionshowed R_(f) =0.30/0.15 iodoplatinate positive, in 30% methanol in ethylacetate. It was filtered through Celite with ethanol and methylenechloride, evaporated, and chromatographed on silica gel using 30%methanol in ethyl acetate as eluant to afford 300 mg (29%) of the lesspolar diastereomer as an oil and 420 mg (41%) of the more polardiastereomer as an oil.

Less polar diastereomer:

¹ H-NMR (δ, CDCl₃): 1.25 (singlet, 9H), 2.18, 2.50 and 3.23 (multiplets,7H), 4.52 and 4.90 (multiplets, 2H), 6.5 (broad singlet, 1H, NH),7.0-7.4 (m, 10H).

¹³ C-NMR (δ, CDCl₃): 28.8, 37.7, 40.5, 51.3, 51.7, 52.7, 60.3, 64,125.6, 126.5, 126.8, 127.8, 128.7, 129.1, 140.7, 145.4, 167.9, 171.

IR (cm.⁻¹, KBr): 1655 (C═O).

More polar diastereomer:

¹ H-NMR (δ, CDCl₃): 1.20 (singlet, 9H), 1.9-2.5 (multiplets, 4H), 3.10(m, 1H), 3.56 (AB_(q), J_(AB) =16, Δν=213, 2H), 4.12 (d, J=16, 1H), 4.99(d, J=10, 1H), 5.68 (broad singlet, 1H, NH), 7.1-7.4 (m, 10H).

¹³ C-NMR (δ, CDCl₃): 28.6, 39.4, 41.8, 46.6, 48.3, 50.8, 53.2, 60.7,126.7, 126.8, 128.5, 128.6, 128.8, 129.5, 138.4, 145.5, 168.0, 177.4.

IR (cm.⁻¹, KBr): 1645 and 1670 (shoulder) (C═O).

MS (%): 393 (parent, 1.4), 265 (17), 193 (24), 132 (100), 91 (27).

H.trans-1-(t-Butylacetamido)-3-(3-tolylureido)-5,7-diphenylhexahydroazepin-2-one

To a 35 mL round-bottomed flask equipped with N₂ inlet were added 150 mg(0.382 mmol)1-(t-butylacetamido)-3-amino-5,7-diphenylhexahydroazepin-2-one (lesspolar diastereomer), 4 mL 1,2-dichloroethane, and 49 mL (0. 382 mmol)3-tolylisocyanate. The reaction was stirred at room temperature for 2.7hours, diluted with 10 volumes of diisopropyl ether, stirred 30 minutes,filtered, washed with diisopropyl ether, and dried to a white solid,M.P. 245°-246° C., 109 mg (54%).

¹ H-NMR (δ, CDCl₃): 1.26 (singlet, 9H), 1.7-2.6 (multiplets, 5H), 2.23(s, 3H), 3.64 (m, 1H), 3.80 (AB_(q), J_(AB) =16, Δν=399, 2H), 4.14 and4.6-4.8 (multiplets, 2H), 6.57 (d, J=9, 1H), 6.70 (d, J=7, 1H), 7.0-7.6(m, 10H), 8.33 (broad singlet, 1H).

IR (cm.⁻¹, KBr): 1673 and 1640 (C═O).

MS (%): 526 (parent, <1), 235 (73), 234 (82), 193 (36), 132 (100), 57(32), 43 (46), 41 (32).

Anal. calc'd for C₃₂ H₃₈ N₄ O₃ •1.75 H₂ O: C 68.86, H 7.49, N 10.04.Found: C 68.90, H 7.25, N 9.86.

EXAMPLE 61trans-1-(t-Butylacetamido)-3-(3-methoxyphenylureido)-5,7-diphenylhexahydroazepin-2-one

Prepared from the less polar amine diastereomer in Example 60G in 49%yield, mp 242°-244° C.

¹ H-NMR (δ, CDCl₃): 1.26 (singlet, 9H), 1.7-2.6 (multiplets, 5H), 3.64(m, 1H), 3.69 (s, 3H), 3.81 (AB_(q), J_(AB) =16, Δν=401, 2H), 4.14 and4.6-4.8 (multiplets, 2H), 6.6-6.9 (multiplets, 2H), 7.0-7.6 (m, 10H),8.34 (broad singlet, 1H).

IR (cm.⁻¹, KBr): 1673 and 1640 (C═O)

MS (%): 542 (parent, 0.9), 348 (16), 305 (68), 235 (58), 234 (65), 149(100), 132 (89), 123 (33), 91 (39), 57 (39), 44 (47).

Anal. calc'd for C₃₂ H₃₈ N₄ O₄ •1.5 H₂ O: C 67.47, H 7.25, N 9.83.Found: C 67.52, H 7.17, N 9.60.

EXAMPLE 62cis-1-(t-Butylacetamido)-3-(3-tolylureido)-5,7-diphenylhexahydroazepin-2-one

Prepared from the more polar amine diastereomer in Example 60G in 68%yield, M.P. 253°-253.5° C.

¹ H-NMR (δ, CDCl₃): 1.15 (singlet, 9H), 1.9-2.7 (multiplets, 4H), 2.22(s, 3H), 3.27 (m, 1H), 3.50 (AB_(q), J_(AB) =16, Δν=224, 2H), 5.09 (dd,J=1,5, 1H), 5.29 (d, J=10, 1H), 6.69 (d, J=7, 1H), 6.83 (d, J=6, 1H),7.0-7.6 (m, 11H).

IR (cm.⁻¹, KBr): 1660 (broad, C═O)

MS (%): 526 (parent, 0.8), 320 (32), 319 (38), 235 (44), 234 (44), 133(100), 132 (91), 57 (41), 44 (36), 41 (38), 39 (33).

Anal. calc'd for C₃₂ H₃₈ N₄ O₃ : C 72.98, H 7.27, N 10.64. Found: C72.94, H 7.31, N 10.45.

EXAMPLE 631-(t-Butylacetamido)-3-(3-methoxyphenylureido)-5,7-diphenylhexahydroazepin-2-one

Prepared from the more polar amine diastereomer in Example 60G in 43%yield, mp 166°-173° C.

¹ H-NMR (δ, CDCl₃): 1.15 (singlet, 9H), 1.9-2.7 (multiplets, 4H), 3.25(m, 1H), 3.52 (AB_(q), J_(AB) =16, Δν=225, 2H), 3.69 (s, 3H), 5.09 (m,1H), 5.29 (d, J=10, 1H), 6.45 (d, J=8, 1H), 6.84 (broad s, 1H), 7.0-7.6(m, 11H).

IR (cm.⁻¹, KBr): 1645 (broad, C═O).

MS (%): 542 (parent, <1), 265 (15), 235 (37), 234 (340), 193 (18), 149(100), 123 915), 91 (41), 78 (18), 57 (16).

Anal. calc'd for C₃₂ H₃₈ N₄ O₄ : C 70.83, H 7.06, N 10.32. Found: C70.66, H 6.80, N 10.32.

EXAMPLE 641-(t-Butylacetamido)-3-(3-chlorophenylureido)-5,7-diphenylhexahydroazepin-2-one

Prepared from the more polar amine diastereomer in Example 60G in 36%yield, M.P. 78°-185° C.

¹ H-NMR (δ, CDCl₃): 1.15 (singlet, 9H), 1.9-2.7 (multiplets, 4H), 3.27(m, 1H), 3.51 (AB_(q), J_(AB) =16, Δν=226, 2H), 5.09 (dd, J=1,5, 1H),5.29 (d, J=10, 1H), 6.9-7.6 (m, 12H), 7.68 (s, 1H).

IR (cm.⁻¹, KBr): 1665 and 1642 (and shoulder at 1682) (C═O).

MS (%): 546/548 (parent, Cl^(35/37), <1), 265 (14), 193 (21), 153/155(100/34, Cl^(35/37)), 115 (21), 91 (28), 90 (25), 58 (29).

Anal. calc'd for C₃₁ H₃₅ N₄ O₃ Cl: C 68.06, H 6.45, N 10.24. Found: C67.73 H 6.13, N 10.07.

HRMS calc'd for C₃₁ H₃₅ N₄ O₃ Cl³⁵ : 546.23895. Found: 546.23581.

EXAMPLE 651-(t-Butylacetamido)-3-(3-ethylphenylureido)-5,7-diphenylhexahydroazepin-2-one

Prepared from the more polar amine diastereomer of Example 60G in 46%yield, M.P. 233°-234° C.

¹ H-NMR (δ, CD₃ SOCD₃): 1.14 (t, J=7, 3H), 1.15 (singlet, 9H), 1.8-2.1(m, 3H), 2.49 (m, 2H), 2.5-2.7 (m, 1H), 3.23 (m, 1H), 3.51 (AB_(q),J_(AB) =16, Δν=225, 2H), 5.07 (m, 1H), 5.28 (d, J=10, 1H), 6.72 (d, J=8,1H), 6.82 (d, J=5, 1H), 7.0-7.6 (m, 14H), 8.94 (bs, 1H).

¹³ C-NMR (δ, CD₃ SOCD₃): 15.6, 22.8, 28.5, 45.0, 47.0, 49.9, 51.5, 59.4,120.6, 126.8, 128.5, 129.4, 139.2, 140.5, 144.2, 146.3, 154.1, 167.3,173.3.

IR (cm.⁻¹, KBr): 1660 (broad, C═O).

MS (%): 540 (parent, 2), 3235 (21), 147 (32), 132 (100), 121 (48), 91(31).

Anal. calc'd for C₃₃ H₄₀ N₄ O₃ •1/2H₂ O: C 72.10, H 7.52, N 10.19.Found: C 72.15, H 7.16, N 9.74 (-0.45).

EXAMPLE 661-(t-Butylacetamido)-3-(3-trifluoromethylphenylureido)-5,7-diphenylhexahydroazepin-2-one

Prepared from the more polar amine diastereomer of Example 60G in 36%yield, M.P. 263°-264° C.

¹ H-NMR (δ, CD₃ SOCD₃): 1.15 (singlet, 9H), 1.8-2.1 (m, 3H), 2.58 (m,1H), 3.23 (m, 1H), 3.51 (AB_(q), J_(AB) =16, Δν=227, 2H), 5.10 (dd,J=1,5, 1H), 5.30 (d, J=10, 1H), 6.95 (d, J=5, 1H), 7.02 (s, 1H), 7.1-7.5(m, 13H), 8.00 (bs, 1H), 9.41 (bs, 1H).

¹³ C-NMR (δ, CD₃ SOCD₃): 28.5, 44.9, 47.0, 50.0, 51.6, 59.4, 126.3,126.8, 128.1, 128.4, 128.5, 129.4, 129.8, 139.2, 141.3, 146.2, 154.0,167.2, 173.1.

IR (cm.⁻¹, KBr): 1660 (broad, C═O).

MS (%): 580 (parent, 5), 262 (50), 193 (62), 187 (65), 132 9100), 91(87), 57 (99).

Anal. calc'd for C₃₂ H₃₅ N₄ O₃ F₃ •1/2H₂ O: C 65.18, H 6.15, N 9.50.Found: C 62.25, H 5.93, N 9.18.

EXAMPLE 671-(t-Butylacetamido)-3-(3-methylthiophenylureido)-5,7-diphenylhexahydroazepin-2-one

Prepared from the more polar amine diastereomer of Example 60G of 49%yield, M.P. 170°-176° C.

¹ H-NMR (δ, CD₃ SOCD₃): 1.15 (singlet, 9H), 1.9-2.1 (m, 3H), 2.41 (s,3H), 2.62 (m, 1H), 3.27 (m, 1H), 3.52 (AB_(q), J_(AB) =16, Δν=226, 2H),5.11 (dd, J=1,5, 1H), 5.30 (d, J=10, 1H), 6.77 (d, J=5, 1H), 6.85 (d,J=5, 1H), 7.0-7.6 (m, 14H), 9.06 (bs, 1H).

¹³ C-NMR (δ, CD₃ SOCD₃): 14.6, 28.5, 44.9, 47.0, 49.9, 51.5, 59.4,114.0, 114.4, 118.5, 126.3, 126.8, 126.9, 128.5, 128.6, 129.2, 129.4,138.5, 139.2, 141.1, 146.2, 154.0, 167.3, 173.2.

IR (cm.⁻¹, KBr): 1660 (broad, C═O).

FAB MS (%): 559 (parent+1, 10), 394 (12), 233 913), 193 914), 155 (97),135 924), 119 (100), 103 (38).

Anal. calc'd for C₃₂ H₃₈ N₄ O₃ S: C 68.79, H 6.85, N 10.03. Found: C68.91, H 6,948, N 9.96.

EXAMPLE 681-(t-Butylacetamido)-3-(3-carboxamidophenylureido)-5,7-diphenylhexahydroazepin-2-one

Prepared from the more polar amine diastereomer of Example 60G in 18%yield, M.P. 155°-165° C.

¹ H-NMR (δ, CDCl₃): 1.145 (singlet, 9H), 2.00 (m, 1H), 2.2-2.5 (m, 3H),3.32 (m, 1H), 3.66 (AB_(q), J_(AB) =16, Δν=73, 2H), 5.25 (bs, 2H), 5.28(m, 1H), 5.76 (m, 1H), 7.1-7.4 (m, 13H), 7.67 (d, J=7, 1H), 7.80 (s,1H), 8.18 (bs, 1H), 9.09 (bs, 1H).

¹³ C-NMR (δ, CDCl₃): 28.6, 38.0, 39.2, 45.7, 47.9, 51.4, 56.7, 61.0,112.7, 118.4, 126.6, 126.8, 127.0, 128.1, 128.2, 128.3, 128.5, 128.6,128.7, 128.8, 129.0, 129.4, 129.5, 129.6, 129.7, 137.8, 139.3, 145.0,167.0, 174.8, 179.9.

IR (cm.⁻¹, KBr ): 1660 (broad, C═O).

FAB MS (%): 555 (parent, 62), 481 (15), 424 (23), 193 (56), 155 (23),119 (100), 103 (38).

Anal. calc'd for C₃₂ H₃₇ N₅ O₄ •1/3H₂ O: C 68.43, H 6.76, N 12.47.Found: C 68.47, H 6.47, N 12.44.

EXAMPLE 691-(t-Butylacetamido)-3-(4-tolylureido)-5,7-diphenylhexahydroazepin-2-one

Prepared from the more polar amine diastereomer in Example 60G in 25%yield, M.P. 156°-165° C.

¹ H-NMR (δ, CD₃ SOCD₃): 1.15 (singlet, 9H), 1.9-2.1 (m, 3H), 2.20 (s,3H), 2.61 (m, 1H), 3.27 (m, 1H), 3.51 (AB_(q), J_(Ab) =16, Δν=225, 2H),5.08 (m, 1H), 5.29 (d, J=10, 1H), 6.78 (d, J=5, 1H), 7.0 and 7.2-7.4 (m,15H), 8.87 (bs, 1H).

¹³ C-NMR (δ, CD₃ SOCD₃): 20.3, 28.5, 45.0, 47.0, 49.9, 51.5, 59.4,117.6, 126.3, 126.8, 128.5, 128.7, 129.1, 129.2, 129.3, 129.4, 129.5,129.7, 138.0, 139.3, 146.3, 154.2, 167.3, 173.4.

IR (cm.⁻¹, KBr): 1660 (broad, C═O).

FAB MS (%): 527 (parent+1, 30), 454 (6), 313 (12), 235 910), 157 (100).

Anal. calc'd for C₃₂ H₃₈ O₃ •2/3H₂ O: C 71.35, H 7.36, N 10.40. Found: C71.20, H 7.26, N 10.23.

EXAMPLE 70 Resolution of1-(N-t-butylacetamido)-3-(3-tolylureido)-5,7-diphenyl-hexahydroazepin-2-one

Carried out in analogy with a procedure developed by Bock, M. G., etal., J. Org. Chem., 52, 3232-3239 (1987) using L-phenylalanine as theresolving agent:

A. 1-(N-t-Butylacetamido)-3-(2-(t-butoxycarbonylamino)-3-phenylpropionamido)-5,7-diphenylhexahydroazepin-2-one

To a 100 mL round-bottomed flask equipped with N₂ inlet were added 650mg (1.65 mmol) of the more polar isomer of1-(t-butylacetamido)-3-amino-5,7-diphenylhexahydroazepin-2-one, 439 mg(1.65 mmol) t-BOC-L-phenylalanine, 253 mg (1.65 mmol)N-hydroxybenzotriazole, 13 mL dry methylene chloride, 317 mg (1.65 mmol)ethyl(dimethylaminopropyl)carbodiimide, and 0.415 mL (2.98 mmol)triethylamine. The reaction was stirred at room temperature for 14 hr,poured into water, and extracted into ethyl acetate. The organic layerwas washed with 1N HCl, water, saturated aqueous sodium bicarbonatesolution, and brine, dried over sodium sulfate, and evaporated. TLCshowed one spot of R_(f) =0.30 in 1/1-ethyl acetate/hexane for theproduct, which was a foam, 950 mg (90%), α_(D) =-5.77° (C=0.8, CH₂ Cl₂).

¹ H-NMR (δ, CDCl₃): 1.20 (singlet, 9H), 1.28 (s, 9H), 1.9-2.2 (m, 3H),2.43 and 2.57 (multiplets for the two diastereomers, 1H), 2.8-3.0 (m,3H), 3.53 and 3.54 (two AB_(q) patterns for each diastereomer, J_(AB)=15 and 15, Δν=198 and 195, 2H), 4.18 and 4.32 (multiplets for the twodiastereomers, 1H), 5.0-5.2 (m, 2H), 5.48 and 5.66 (broad singlets foreach diastereomer, 1H), 7.0-7.4 (m, 17H).

¹³ C-NMR (δ, CDCl₃): (pairs of peaks were observed because of the twodiastereomers) 28.2 and 28.6, 38.6 and 39.0, 45.8 and 45.9, 48.0 and48.2, 50.9 and 51.0, 51.4 and 51.5, 55.2 and 55.8, 60.3, 61.1 and 61.2,126.7, 126.8, 126.9, 128.6, 128.8, 128.9, 129.3, 129.5, 129.6, 129.7,129.8, 130.0, 138.0, 138.2, 145.0, 145.2, 167.3 and 167.4, 170.2 and170.5, 171.0 and 171.05, 173.0 and 173.1.

IR (cm.⁻¹, KBr): 1723, 1667, and 1635 (C═O).

MS (%): 640 (parent, 0.35), 452 (27), 376 (32), 264 (26), 193 (46), 120(100), 91 (92).

B.1-(N-t-Butylacetamido)-3-(2-amino-3-phenylpropionamido)-5,7-diphenyl-hexahydroazepin-2-one

To a 125 mL round-bottomed flask equipped with N₂ inlet were added 950mg (1.49 mmol)1-(N-t-butylacetamido)-3-(2-(t-butoxycarbonylamino)-3-phenylpropionamido)-5,7-diphenylhexahydroazepin-2-one(mixture of diastereomers) and 40 mL ethyl acetate. The solution wascooled to 0° C., saturated with HCl gas, and stirred at 0° C. for 20minutes, then at room temperature for 40 minutes. The reaction waspoured into aqueous sodium bicarbonate solution, diluted with ethylacetate, and the organic layer washed with additional aqueous sodiumbicarbonate solution and brine, dried over sodium sulfate, andevaporated. The diastereomeric products were separated by chromatographyon silica gel using ethyl acetate/methanol as eluant to afford eachdiastereomer as an oil.

Less polar diastereomer (R_(f) =0.4 in 10% methanol in ethyl acetate):α_(D=) ⁻ 28.2° (C=1.5, CH₂ Cl₂), 50% yield.

¹ H-NMR (δ, CDCl₃): 1.24 (singlet, 9H), 1.8-2.6 (series of multiplets,4H), 3.1 (m, 3H), 3.58 (AB_(q), J_(AB) =16, Δν=202, 2H), 3.59 (m, 1H),4.18 and 4.32 (multiplets for the two diastereomers, 1H), 5.12 (d, J=10,1H), 5.17 (m, 1H), 5.49 (bs, 1H), 7.0-7.4 (m, 15H), 8.49 (d, J=7, 1H).

¹³ C-NMR (δ, CDCl₃): 28.7, 39.2, 41.1, 46.0, 48.1, 51.0, 56.5, 60.3,61.2, 126.7, 126.8, 127.0, 128.4, 128.6, 128.9, 129.0, 129.3, 129.5,137.8, 138.1, 145.2, 167.5, 173.5.

IR (cm.⁻¹, KBr): 1665 and 1635 (C═O)

MS (%): 540 (parent, 3), 449 (32), 376 (41), 264 (35), 193 (38), 120(100), 91 (43).

More polar diastereomer (R_(f) =0.2 in 10% methanol in ethyl acetate):α_(D) =-32.2° (C=1.5, CH₂ Cl₂), 50% yield.

¹ H-NMR (δ, CDCl₃): 1.23 (singlet, 9H), 1.8-2.6 (series of multiplets,4H), 3.1 (m, 3H), 3.55 (m, 1H), 3.58 (AB_(q), J_(AB) =16, Δν=220, 2H),4.18 and 4.32 (multiplets for the two diastereomers, 1H), 5.10 (d, J=10,1H), 5.17 (m, 1H), 5.49 (bs, 1H), 7.0-7.4 (m, 15H), 8.30 (d, J=7, 1H).

¹³ C-NMR (δ, CDCl₃): 28.7, 39.2, 41.2, 46.0, 48.1, 51.0, 56.9, 60.3,61.2, 126.7, 126.8, 127.0, 128.4, 128.6, 128.9, 129.0, 129.3, 129.5,138.1, 138.2, 145.1, 167.5, 173.5.

IR (cm.⁻¹, KBr): 1665 and 1635 (C═O)

MS (%): 540 (parent, 2), 449 (37), 376 (53), 264 (35), 193 (35), 120(100), 91 (42).

C. (-)-1-(N-t-butylacetamido)-3-amino-5,7-diphenylhexahydroazepin-2-one

To a 100 mL round-bottomed flask equipped with N₂ inlet and condenserwere added 0.40 g (0.745 mmol)1-(N-t-butylacetamido)-3-(2-amino-3-phenylpropionamido)-5,7-diphenyl-hexahydroazepin-2-one(more polar isomer from above), 8 mL 1,2-dichloroethane, and 0.093 mL(0.782 mmol) phenylisothiocyanate. The reaction was refluxed for 1 hr,cooled, and evaporated. The residue was taken up in 10 mLtrifluoroacetic acid and heated at 70°-80° C. for 2 hr. The reaction wascooled, and the product precipitated as a salt with ether and hexane.The precipitate was collected, dissolved in ethyl acetate, washed withaqueous sodium bicarbonate solution and brine, dried over sodiumsulfate, and evaporated. The oil solidified from chloroform to give mp204°-205° C., 0.30 g (100%), α_(D) =-3.72° (C=0.5, TFA). ¹ H-NMR and ¹³C-NMR spectra match those of the racemate.

D. (+)-1-(N-t-butylacetamido)-3-amino-5,7-diphenylhexahydroazepin-2-one

Prepared as above from1-(N-t-butylacetamido)-3-(2-amino-3-phenylpropionamido)-5,7-diphenylhexahydroazepin-2-one(less polar isomer) as an oil in 92% yield, α_(D) =+3.21° (c=0.8, ethylacetate). The ¹ H-NMR spectrum matches that of the racemate.

E.(-)-1-(N-t-butylacetamido)-3-(3-tolylureido)-5,7-diphenylhexahydroazepin-2-one

To a 35 mL round-bottomed flask equipped with N₂ inlet and condenserwere added 293 mg (0.745 mmol)(-)-1-(N-t-butylacetamido)-3-amino-5,7-diphenylhexahydroazepin-2-one, 10mL ethyl acetate, and 0.096 mL (0.745 mmol) m-tolylisocyanate. Thereaction was refluxed for 2.5 hr, cooled, and evaporated. The residuewas chromatographed on silica gel using hexane/ethyl acetate as eluantto afford an oil which was crystallized from methylenechloride/isopropyl ether to a give mp 140°-150° C., 71 mg (18%), α_(D)=-18.6° (c=1, CH₂ Cl₂). The R_(f) value on TLC and ¹ H-NMR spectrummatch those of the racemate.

Anal. calc'd for C₃₂ H₃₈ N₄ O₃ •1/2H₂ O: C 71.75, H 7.34, N 10.46.Found: C 71.66, H 6.75 (-0.59), N 10.29.

F.(+)-1-(N-t-butylacetamido)-3-(3-tolylureido)-5,7-diphenyl-hexahydroazepin-2-one

Prepared as above from(+)-1-(N-t-butylacetamido)-3-amino-5,7-diphenyl-hexahydroazepin-2-one asan oil in 30% yield, which was crystallized from methylenechloride/isopropyl ether to a give mp 140°-150° C., in 15% yield, α_(D)=+18.2° (c=1, CH₂ Cl₂). The R_(f) value on TLC and ¹ H-NMR and ¹³ C-NMRspectra match those of the racemate.

Anal. calc'd for C₃₂ H₃₈ N₄ O₃ •1/2H₂ O: C 71.75, H 7.34, N 10.46.Found: C 71.65, H 6.89 (-0.45), N 10.49.

EXAMPLE 71(1-t-Butoxycarbonylmethyl)-3-(3-tolylureido)-7-cyclohexylhexahydroazepin-2-one

Prepared from(1-t-butoxycarbonylmethyl)-3-amino-7-cyclohexyl-hexahydroazepin-2-one asin Example 11 in 31% yield, M.P. 108°-110° C.

¹ H-NMR (δ, CDCl₃): 0.8-1.0 (m, 2H), 1.1-1.3 (m, 4H), 1.37 (s, 9H),1.6-1.9 (m, 10H), 2.08 (m, 1H), 2.25 (s, 3H), 3.42 (t, J=7, 1H), 3.88(AB_(q), J_(AB) =17, Δν=180, 2H), 5.01 (m, 1H), 6.65 and 7.1-7.4 (m, 6H(includes broad singlets for 2 NH signals)).

¹³ C-NMR (δ, CDCl₃): 21.5, 25.7, 25.9, 26.0, 26.2, 27.2, 28.0, 30.1,31.7, 32.2, 39.4, 45.6, 51.5, 63.4, 81.8, 123.6, 128.7, 138.7, 139.1,155.2, 168.4.

IR (cm.⁻¹, KBr): 1730 (CO₂ R) and 1640 (CONR)

MS (%): 457 (2, parent), 295 (23), 185 (23), 107 (100).

HRMS calc'd for C₂₆ H₄₀ N₃ O₄ : 458.2984. Found: 458.3057.

EXAMPLE 721-t-Butoxycarbonylmethyl)-3-((3-trifluoromethylphenyl)ureido)-7-cyclohexylhexahydroazepin-2-one

Prepared from(1-t-butoxycarbonylmethyl)-3-amino-7-cyclohexyl-hexahydroazepin-2-one asin Example 11 in 36% yield, M.P. 114°-117° C.

¹ H-NMR (δ, CDCl₃): 0.8-1.0 (m, 2H), 1.1-1.3 (m, 4H), 1.34 (s, 9H),1.6-1.9 (m, 10H), 2.0 (m, 1H), 3.48 (t, J=7, 1H), 3.90 (AB_(q), J_(AB)=17, Δν=160, 2H), 5.04 (m, 1H), 6.8-8.0 (series of multiplets, 6H).

¹³ C-NMR (δ, CDCl₃): 25.7, 25.8, 26.0, 26.1, 27.1, 27.9, 30.1, 31.56,31.63, 39.5, 45.7, 51.3, 63.5, 82.0, 129.1, 140.2, 154.8, 168.3, 175.9(not all aromatic carbons could be assigned).

IR (cm.⁻¹, KBr): 1730 (CO₂ R) and 1638 (CONR).

MS (%): 511 (<1, parent), 295 (82), 195 (28), 185 (99), 161 (100), 57(97).

HRMS calc'd for C₂₆ H₃₇ N₃ O₄ F₃ : 512.2732. Found: 512.2751.

EXAMPLE 73(1-t-Butoxycarbonylmethyl)-3-(3-tolylureido)-5,7-diphenylhexahydroazepin-2-one

Prepared from(1-t-butoxycarbonylmethyl)-3-amino-5,7-diphenyl-hexahydroazepin-2-one asin Example 60 as a foam in 6.3% yield.

¹ H-NMR (δ, CDCl₃): 1.2-1.4 (m, 2H), 1.29 (s, 9H), 2.0-2.2 and 2.4-2.6(m, 2H), 2.25 (s, 3H), 3.21 (m, 1H), 3.60 (AB_(q), J_(AB) =18, Δν=160(2H), 5.15 (m, 1H), 5.22 (m, 1H), 6.8 and 7.0-7.4 (m, 16H).

IR (cm.⁻¹, KBr): 1723 (CO₂ R) and 1638 (CONR).

MS (%): 527 (15, parent), 235 (30), 133 (100)

HRMS calc'd for C₃₂ H₃₇ N₃ O₄ : 527.2822. Found: 527.2742.

EXAMPLE 74(1-t-Butoxycarbonylmethyl)-3-(3-tolylureido)-5-phenyl-7-benzylhexahydroazepin-2-one

A. 2-Benzyl-4-phenylcyclohexanone

Prepared in analogy with a procedure developed by Stork, G. and Dowd, S.J. Am. Chem. Soc., 85, 2178 (1963). To a 250 mL round-bottomed flaskequipped with N₂ inlet, Dean-Stark trap, and condenser were added 8.71 g(50 mmol) 4-phenylcyclohexanone, 5.72 mL (50 mmol) cyclohexylamine, and100 mL benzene. The solution was refluxed until water removal wascomplete (12 hours). Twenty mL of this solution, upon cooling, was addedto 10.0 mL of a 1.0M solution of ethyl magnesium bromide intetrahydrofuran, and the reaction heated to 60°-70° C. for 30 minutes.The solution was cooled, and 1.43 mL (12 mmol) benzyl bromide added,producing an immediate color change. The reaction was refluxed 3.5hours, cooled, and evaporated. The residue was taken up in 40 mL 1N HCl,stirred at room temperature 18 hours, and extracted into ethyl acetate,which was washed with water and brine, dried over sodium sulfate, andevaporated. The crude yellow oil was used without further purification,3.2 g (100%).

¹ H-NMR (d, CDCl₃): 1.62 (m, 1H), 1.95 (m, 1H), 2.20 (m, 2H), 2.41 (dd,J=8.5, 14, 1H), 2.55 (m, 2H), 2.77 (m, 1H), 3.01 (m, 1H), 3.34 (dd, J=4,14, 1H), 7.0-7.4 (m, 10H).

IR (cm.⁻¹, KBr): 1715 (C═O).

MS (%): 264 (parent, 38), 235 (10), 159 (16), 146 (28), 145 (26), 131(31), 104 (35), 91 (100).

B. 5-Phenyl-7-benzylhexahydroazepin-2-one

To a 250 mL round-bottomed flask equipped with condenser and N₂ inletwere added 2.64 g (10 mmol) of 2-benzyl-4-phenylcyclohexanone, 1.70 g(15 mmol) hydroxylamine-O-sulfonic acid, and 50 mL formic acid. Thereaction was refluxed 5.5 hours, cooled, and poured into 3N NaOH. Themixture was extracted into ethyl acetate, washed with brine, dried, andevaporated. The residue was chromatographed on silica gel usingmethanol/methylene chloride, collecting the product spot at R_(f) =0.30as an oil, 1.8 g (64%).

¹ H-NMR (d, CDCl₃): 1.6-2.0 (m, 4H), 2.57 (m, 1H), 2.7-2.9 (m, 4H), 3.76(m, 1H), 5.6 and 5.75 (broad singlets, NH, 1H), 7.0-7.4 (m, 10H).

IR (cm.⁻¹, KBr): 1660 (C═O)

MS (%): 279 (parent, 13), 235 (24), 188 (40), 91 (100), 44 (31).

The remaining steps were carried out as described in Example 60:

C. 3-Bromo-5-phenyl-7-benzylhexahydroazepin-2-one

Oil, mixture of 4 diastereomers, 27% yield.

¹ H-NMR (δ, CDCl₃): 1.7-3.2 (series of multiplets, 5H), 2.86 (m, 2H),3.8 and 4.2 (multiplets, 1H), 4.58 and 4.88 (multiplets, 1H), 6.28,6.55, 6.68 and 6.80 (broad singlets, NH, 1H), 7.0-7.4 (m, 10H).

¹³ C-NMR (δ, CDCl₃): the 4 diastereomers gave many overlapping peaks; 3of the 4 lactam carbonyls appeared at 170.35, 170.54, and 170.65.

IR (cm.⁻¹, KBr): 1670 (C═O).

MS (%): 358/360 (parent, Br⁷⁹ /Br⁸¹ 2/2), 266/268 (98/100), 222 (20),158 (45), 144 (53).

D.1-(t-Butylcarbonylmethyl)-3-bromo-5-phenyl-7-benzylhexahydroazepin-2-one

Oil, mixture of 2 diastereomers in a 2/1 ratio, 97% yield.

¹ H-NMR (d, CDCl₃): 1.44 and 1.45 (singlets, 9H), 1.8-4.3 (series ofmultiplets, 8H), 4.9 to 5.4 (multiplets, 1H), 7.0-7.4 (m, 10H).

IR (cm.⁻¹, KBr): 1745 and 1650 (C═O).

MS (%): 392 (parent-Br, 2), 372 (30), 255 (100), 200 (70), 180 (98).

E.1-(t-Butylcarbonylmethyl)-3-azido-5-phenyl-7-benzylhexahydroazepin-2-one

Oil, mixture of 2 diastereomers in a 7/3 ratio, 87% yield.

¹ H-NMR (δ, CDCl₃): 1.45 and 1.46 (singlets, 9H), 1.8-4.6 (series ofmultiplets, 9H), 7.0-7.4 (m, 10H).

IR (cm.⁻¹, KBr): 2107 (N₃), 1739 and 1659 (C═O).

MS (%): 406 (parent-N₂, 2), 350 (10), 259 (13), 91 (17), 57 (16), 32(100).

F.1-(t-Butylcarbonylmethyl)-3-amino-5-phenyl-7-benzylhexahydroazepin-2-one

Oil, predominantly one diastereomer, 67% yield.

¹ H-NMR (δ, CDCl₃): 1.42 and 1.46 (singlets, 9H), 1.5-2.0 (m, 4H), 2.32and 2.71 (multiplets, 1H), 3.08 (m, 2H), 3.25 (m, 1H), 4.1 (m, 1H), 4.10(AB_(q), J_(AB) =17, Δν=75), 7.0-7.4 (m, 10H).

¹³ C-NMR (δ, CDCl₃): (one diastereomer) 28.1, 39.1, 39.3, 44.7, 51.8,54.3, 55.4, 63.3, 81.6, 126.7, 126.9, 127.2, 128.5, 128.8, 137.3, 144.6,169.1, 176.0.

MS (%): 409 (parent+1, 2), 262 (42), 132 (100), 91 (30).

G.(1-t-Butoxycarbonylmethyl)-3-(3-tolylureido)-5-phenyl-7-benzylhexahydroazepin-2-one

9% yield, M.P. 100°-110° C.

¹ H-NMR (δ, CDCl₃): 1.41 (s, 9H), 1.5-3.2 (series of multiplets, 7H),4.15 (AB_(q), J_(Ab) =17, Δν=139), 4.28 (m, 1H), 5.24 (m, 1H), 6.8 and7.0-7.4 (m, 16H).

¹³ C-NMR (δ, CDCl₃): 21.5, 28.0, 38.2, 39.3, 39.35, 39.4, 44.5, 50.4,55.6, 81.9, 127.0, 127.3, 128.5, 128.6, 128.7, 128.9, 129.0, 136.7,138.9, 144.4, 155.3, 168.6, 173.

IR (cm.⁻¹, KBr): 1740 (CO₂ R) and 1640 (CONR).

MS (%): 541 (parent, 2), 261 (30), 132 (100), 91 (47).

Anal. calc'd for C₃₃ H₃₉ N₃ O₄ : C 73.17, H 7.26, N 7.76. Found: C72.82, H 7.28, N 7.71.

EXAMPLE 75(1-t-Butoxycarbonylmethyl)-3-(3-methoxyphenylureido)-5-phenyl-7-benzylhexahydro-azepin-2-one

Prepared from the title compound of Example 74F in analogy with theprocedure of Example 60, in 27% yield, M.P. 95°-105° C.

¹ H-NMR (δ, CDCl₃): 1.40 (s, 9H), 1.5-3.2 (series of multiplets, 7H),3.72 (s, 3H), 4.10 (AB_(q), J_(AB) =17, Δν=135), 4.28 (m, 1H), 5.24 (m,1H), 6.5, 6.8 and 7.0-7.6 (m, 16H).

¹³ C-NMR (δ, CDCl₃): 28.0, 38.2, 39.2, 39.3, 39.4, 44.5, 50.4, 55.2,55.7, 82.0, 105.4, 109.2, 112.2, 126.9, 127.0, 127.2, 127.3, 128.5,128.6, 128.7, 128.9, 129.1, 129.2, 129.3, 129.5, 129.6, 136.7, 140.4,144.4, 155.2, 160.2, 168.6, 172.9.

IR (cm.⁻¹, KBr): 1740 (CO₂ R) and 1640 (CONR).

MS (%): 557 (parent, 1), 261 (35), 149 (100), 132 (98), 123 (53), 91(52).

Anal. calc'd for C₃₃ H₃₉ N₃ O₅ : C 71.07, H 7.05, N 7.53. Found: C71.30, H 7.10, N 7.34.

EXAMPLE 76(1-t-Butoxycarbonylmethyl)-3-(3-chlorophenylureido)-5-phenyl-7-benzylhexahydroazepin-2-one

Prepared from the title compound of Example 74F in analogy with theprocedure of Example 60 in 33% yield, M.P. 95°-110° C.

¹ H-NMR (δ, CDCl₃): 1.38 (s, 9H), 1.5-3.2 (series of multiplets, 7H),4.10 (AB_(q), J_(AB) =17, Δν=138), 4.38 (m, 1H), 5.28 (m, 1H), 6.8-7.8(m, 16H).

¹³ C-NMR (δ, CDCl₃): 28.0, 37.5, 39.1, 39.2, 39.5, 50.3, 55.7, 60.4,82.1, 117.3, 119.4, 122.3, 122.4, 126.5, 126.7, 127.0, 127.1, 127.2,128.5, 128.6, 128.8, 128.9, 129.2, 129.3, 129.7, 134.4, 136.6, 140.6,144.2, 155.0, 168.5, 173.6.

IR (cm.⁻¹, KBr): 1740 (CO₂ R) and 1640 (CONR).

MS (%): 562 (parent, 1), 261 (50), 153 (80), 132 (100), 91 (40).

HRMS calc'd for C₃₂ H₃₇ N₃ O₄ Cl: 562.24765. Found: 562.24970.

Anal. calc'd for C₃₂ H₃₆ N₃ O₄ Cl: C 68.38, H 6.46, N 7.48. Found: C68.37, H 6.76, N 7.02 (-0.46).

EXAMPLE 77(1-t-Butoxycarbonylmethyl)-3-(3-tolylureido)-5-phenyl-7-cyclohexylmethyl-hexahydroazepin-2-one

Prepared from(1-t-butoxycarbonylmethyl)-3-amino-5-phenyl-7-cyclohexylmethylhexahydroazepin-2-oneby a procedure analogous to that of Example 74 in 47% yield as a foam,mixture of diastereomers.

¹ H-NMR (δ, CDCl₃): 1.37 (s, 9H), 0.8-2.3 and 2.64 (series ofmultiplets, 7H), 3.18 (m, 1H), 3.95 and 4.0 (AB_(q) 's, J_(AB) =17 and17, Δν=139 and 150), 4.0-4.1 (m, 1H), 5.12 and 5.23 (multiplets, 1H),6.8 and 7.0-7.5 (m, 16H).

¹³ C-NMR (δ, CDCl₃): (one diastereomer) 21.5, 26.1, 28.0, 33.3, 33.5,34.6, 39.2, 39.3, 39.9, 41.5, 44.9, 46.0, 51.9, 54.2, 81.8, 117.1,120.8, 123.6, 123.8, 126.3, 126.4, 126.9, 127.2, 128.5, 128.7, 138.7,139.1, 144.8, 145.6, 155.1, 168.5, 173.3.

IR (cm.⁻¹, KBr): 1740 (CO₂ R) and 1640 (CONR).

MS (%): 547 (parent, 1), 243 (15), 184 (50), 141 (30), 136 (100).

Anal. calc'd for C₃₃ H₄₅ N₃ O₄ : C 72.36, H 8.28, N 7.67. Found: C72.21, H 8.35, N 7.44.

EXAMPLE 78(1-t-Butoxycarbonylmethyl)-3-(3-tolylureido)-5-phenyl-7-cyclohexylhexahydroazepin-2-one

Prepared from(1-t-butoxycarbonylmethyl-3-amino-5-phenyl-7-cyclohexylhexahydroazepin-2-oneby a procedure analogous to that of Example 74 in 6% yield as a 3/1mixture of diastereomers, foam.

¹ H-NMR (δ, CDCl₃): 0.8-2.3 (m, 15H), 1.37 (s, 9H), 2.26 (s, 3H), 3.02and 3.22 (multiplets, 1H), 3.6 (m, 1H), 4.01 and 4.1 (AB_(q) 's, J_(AB)=17 and 17, Δν=216 and 230, 2H), 4.92 and 5.13 (multiplets, 1H), 6.7-7.4(m, 11H).

¹³ C-NMR (d, CDCl₃): (one diastereomer) 21.5, 25.86, 25.90, 26.1, 28.0,31.5, 39.4, 39.9, 45.8, 46.6, 51.6, 63.1, 81.9, 117.2, 120.8, 120.9,123.6, 123.8, 126.4, 126.9, 127.0, 128.5, 128.6, 128.7, 128.8, 138.8,139.0, 145.9, 155.1, 168.2, 175.5.

IR (cm.⁻¹, KBr): 1730 (CO₂ R) and 1640 (CONR).

MS (%): 533 (parent, 2), 240 (25), 133 (100), 107 (70), 91 (40).

HRMS calc'd for C₃₂ H₄₃ N₃ O₄ : 533.3243. Found: 533.32941.

EXAMPLE 79(1-t-Butoxycarbonylmethyl)-3-(3-methoxyphenylureido)-5-phenyl-7-cyclohexyl-hexahydroazepin-2-one

Prepared from(1-t-butoxycarbonylmethyl)-3-amino-5-phenyl-7-cyclohexylhexahydroazepin-2-oneby a procedure analogous to that of Example 74 in 14% yield, as amixture of diastereomers, foam.

¹ H-NMR (δ, CDCl₃): 0.8-2.3 (m, 15H), 1.37 (s, 9H), 2.6 (m, 1H), 3.0-3.4(m, 1H), 3.74 (s, 3H), 3.97 and 4.1 (AB_(q) 's, J_(AB) =17 and 17,Δν=213 and 240, 2H), 4.90 and 5.12 (multiplets, 1H), 6.5 and 6.8-7.4 (m,11H).

¹³ C-NMR (δ, CDCl₃): (one diastereomer) 25.9, 26.3, 28.0, 31.0, 34.9,42.5, 45.8, 46.6, 51.5, 55.2, 63.1, 64.7, 81.8, 109.0, 126.2, 126.3,126.9, 127.0, 128.5, 128.6, 129.5, 129.6, 140.5, 145.9, 147.1, 154.9,160.2, 168.3, 175.4

IR (cm.⁻¹, KBr): 1730 (CO₂ R) and 1640 (CONR).

MS (%): 549 (parent, 3.5), 344 (25), 240 (30), 149 (60), 132 (100).

HRMS calc'd for C₃₂ H₄₃ N₃ O₄ : 549.3192. Found: 549.33256.

EXAMPLE 80cis-1-(t-Butylacetamido)-3-(3-tolylureido)-5-phenyl-7-(4-fluorophenyl)hexahydroazepin-2-one

Prepared fromcis-1-(t-butylacetamido)-3-amino-5-phenyl-7-(4-fluorophenyl)-hexahydroazepin-2-oneby a procedure analogous to that of Example 60 in 63% yield, M.P.228°-232° C.

¹ H-NMR (δ, CD₃ SOCD₃): 1.16 (singlet, 9H), 2.0 (m, 3H), 2.24 (s, 3H),2.5 (m, 1H), 3.1-3.9 (multipliers, 3H), 5.10 (m, 1H), 5.34 (m, 1H),6.6-7.5 (m, 14H), 8.95 (bs, 1H). ¹³ C-NMR (δ, CD₃ SOCD₃): 21.3, 28.4,45.0, 50.0, 51.6, 58.5, 114.7, 115.1, 115.4, 118.1, 121.8, 122.4, 126.3,126.8, 128.5, 131.6, 131.7, 135.5, 137.8, 140.5, 146.2, 154.1, 167.2,173.4.

IR (cm.⁻¹, KBr): 1660 (broad, C═O).

FAB MS (%): 545 (parent+1, 43), 472 (36), 412 (37), 254 (27), 211 (100).

Anal. calc'd for C₃₂ H₃₇ N₄ O₃ F•3/4H₂ O: C 68.86, H 6.95, N 10.04.Found: C 68.87, H 6.86, N 9.69.

EXAMPLE 81cis-1-(t-Butylacetamido)-3-(3-methoxyphenylureido)-5-phenyl-7-(4-fluorophenyl)-hexahydroazepin-2-one

Prepared fromcis-1-(t-butylacetamido)-3-amino-5-phenyl-7-(4-fluorophenyl)-hexahydroazepin-2-oneby a procedure analogous to that of Example 60 in 54% yield, M.P.22.5°-227° C.

¹ H-NMR (δ, CD₃ SOCD₃): 1.16 (singlet, 9H), 2.0 (m, 3H), 2.6 (m, 1H),3.2-3.9 (m, 3H), 3.70 (s, 3H), 5.10 (m, 1H), 5.32 (m, 1H), 6.5 and6.8-7.5 (m, 14H), 9.05 (bs, 1H).

¹³ C-NMR (δ, CD₃ SOCD₃): 28.4, 44.9, 46.8, 50.0, 51.5, 54.9, 58.5,103.2, 106.5, 109.9, 115.1, 115.4, 126.3, 126.8, 128.5, 129.4, 131.6,141.8, 146.1, 154.1, 159.7, 167.2, 173.3.

IR (cm.⁻¹, KBr): 1660 (broad, C═O).

FAB MS (%): 561 (parent+1, 25), 488 (30), 412 (28), 254 (27), 211 (100).

Anal. calc'd for C₃₂ H₃₇ N₄ O₄ •H₂ O: C 66.42, H 6.79, N 9.68. Found: C66.36, H 6.57, N 9.42.

EXAMPLE 82cis-1-(t-Butylacetamido)-3-(3-chlorophenylureido)-5-phenyl-7-(4-fluorophenyl)-hexahydroazepin-2-one

Prepared fromcis-1-(t-butylacetamido)-3-amino-5-phenyl-7-(4-fluorophenyl)hexahydroazepin-2-oneby a procedure analogous to Example 60 in 44% yield, M.P. 175°-178° C.

¹ H-NMR (δ, CD₃ SOCD₃): 1.16 (singlet, 9H), 2.0 (m, 3H), 2.6 (m, 1H),3.2-3.9 (m, 3H), 5.10 (m, 1H), 5.32 (m, 1H), 6.8-7.6 (m, 14H), 9.27 (bs,1H).

¹³ C-NMR (δ, CDCl₃): 28.45, 44.9, 46.8, 50.0, 51.6, 58.5, 115.1, 115.4,115.8, 116.8, 120.7, 126.4, 126.8, 128.6, 130.3, 131.6, 131.7, 133.2,135.4, 142.1, 146.1, 153.9, 167.2, 173.2.

IR (cm.⁻¹, KBr): 1660 (broad, C═O).

FAB MS (%): 565 (parent, 20), 492 (26), 412 (27), 254 (20), 211 (100).

Anal. calc'd for C₃₁ H₃₄ N₄ O₃ FCl•2H₂ O: C 61.94, H 6.37, N 9.32.Found: C 61.93, H 5.73 (-0.64), N 9.09.

HRMS calc'd for C₃₁ H₃₄ N₄ O₃ FCl: 564.2790. Found: 564.23444.

EXAMPLE 83cis-1-(t-Butylacetamido)-3-(3-tolylureido)-5-phenyl-7-(4-chlorophenyl)hexahydroazepin-2-one

Prepared fromcis-1-(t-butylacetamido)-3-amino-5-phenyl-7-(4-chlorophenyl)hexahydroazepin-2-oneby a procedure analogous to that of Example 60 in 69% yield, M.P.224°-226° C.

¹ H-NMR (δ, CDCl₃, TFA): 1.20 (singlet, 9H), 2.0 (m, 1H), 2.3 (m, 3H),2.33 (s, 3H), 3.30 (m, 1H), 3.98 (AB_(q), J_(AB) =16, Δν=43, 2H), 5.27(m, 1H), 5.38 (d, J=11, 1H), 6.69 (d, J=7, 1H), 6.9-7.5 (m, 16H).

¹³ C-NMR (δ, CDCl₃, TFA): 22.0, 27.9, 38.5, 38.8, 45.6, 52.8, 61.0,112.4, 116.1, 119.9, 126.6, 127.3, 128.9, 129.5, 129.8, 130.8, 134.9,143.6, 158, 176.

IR (cm.⁻¹, KBr): 1660 (broad, C═O).

FAB MS (%): 561 (parent+1, 47), 488 (30), 454 (20), 428 (25), 227 (28),157 (100), 119 (46).

Anal. calc'd for C₃₂ H₃₇ N₄ O₃ Cl•1/2H₂ O: C 67.41, H 6.72, N 9.83.Found: C 67.77, H 6.57, N 9.44.

EXAMPLE 84cis-1-(t-Butylacetamido)-3-(3-methoxyphenylureido)-5-phenyl-7-(4-chlorophenyl)-hexahydroazepin-2-one

Prepared fromcis-1-(t-butylacetamido)-3-amino-5-phenyl-7-(4-chlorophenyl)hexahydroazepin-2-oneby a procedure analogous to that of Example 60 in 33% yield, M.P.130°-132° C.

¹ H-NMR (δ, CDCl₃, TFA): 1.21 (singlet, 9H), 2.0-2.4 (multiplets, 4H),3.29 (m, 1H), 3.82 (s, 3H), 3.89 (AB_(q), J_(AB) =16, Δν=77, 2H), 5.24(m, 1H), 5.39 (d, J=11, 1H), 6.7-6.9 and 7.1-7.4 (m, 16H).

¹³ C-NMR (δ, CDCl₃, TFA): 28.0, 38.7, 38.9, 45.6, 48.3, 52.6, 52.8,55.5, 60.8, 126.6, 127.3, 128.9, 129.5, 130.4, 130.5, 130.8, 135.1,135.6, 143.8, 160.2, 168.8, 175.7.

IR (cm.⁻¹, KBr): 1660 (broad, C═O).

FAB MS (%): 577 (parent, 82), 504 (61), 428 (56), 227 (76), 119 (100),103 (55).

Anal. calc'd for C₃₂ H₃₇ N₄ O₄ Cl: C 66.60, H 6.46, N 9.71. Found: C66.83, H 6.46, N 9.51.

EXAMPLE 85cis-1-(t-Butylacetamido)-3-(3-chlorophenylureido)-5-phenyl-7-(4-chlorophenyl)hexa-hydroazepin-2-one

Prepared in analogy with Example 60 in 52% yield, M.P. 229°-231° C.

¹ H-NMR (δ, CDCl₃, TFA): 1.21 (singlet, 9H), 2.0-2.4 (multiplets, 4H),3.29 (m, 1H), 3.92 (AB_(q), J_(AB) =16, Δν=65, 2H), 5.27 (d, J=8, 1H),5.43 (d, J=10, 1H), 7.1-7.5 (m, 16H).

¹³ C-NMR (δ, CDCl₃, TFA): 22.0, 27.9, 38.7, 45.6, 48.3, 52.5, 60.9,71.3, 126.1, 126.6, 127.3, 128.9, 129.5, 130.6, 130.8, 134.9, 135.3,135.7, 143.7, 176.0.

IR (cm.⁻¹, KBr): 1660 (broad, C═O).

FAB MS (%): 581 (parent+1, 63), 508 (61), 428 (36), 227 (65), 157 (81),119 (100).

Anal. calc'd for C₃₁ H₃₄ N₄ O₃ Cl₂ •1/3H₂ O: C 63.37, H 5.95, N 9.54.Found: C 63.74, H 5.99, N 8.87 (-0.67).

HRMS calc'd for C₃₁ H₃₄ N₄ O₃ Cl₂ : 580.2008. Found: 580.19940.

EXAMPLE 86cis-1-(t-Butylacetamido)-3-(3-tolylureido)-5-phenyl-7-(4-tolyl)hexahydroazepin-2-one

Prepared fromcis-1-(t-butylacetamido)-3-amino-5-phenyl-7-(4-tolyl)hexahydroazepin-2-oneby a procedure analogous to that of Example 60 in 57% yield, M.P.216°-218° C.

¹ H-NMR (δ, CDCl₃, TFA): 1.20 (singlet, 9H), 2.0-2.4 (multiplets, 4H),2.33 (s, 3H), 2.34 (s, 3H), 3.27 (m, 1H), 3.96 (AB_(q), J_(AB) =16,Δν=62, 2H), 5.22 (d, J=10, 1H), 5.39 (d, J=10, 1H), 7.0-7.4 (m, 16H).

¹³ C-NMR (δ, CDCl₃, TFA): 20.9, 22.0, 27.9, 38.5, 38.9, 45.7, 48.2,52.8, 61.5, 71.3, 120.8, 124.5, 126.6, 127.2, 128.0, 128.9, 129.3,129.8, 130.0, 133.4, 134.7, 139.7, 140.4, 143.9, 176.

IR (cm.⁻¹, KBr): 1660 (broad, C═O).

FAB MS (%): 541 (parent+1, 10), 207 (12), 157 (100), 119 (24), 103 (12).

Anal. calc'd for C₃₃ H₄₀ N₄ O₃ : C 73.30, H 7.46, N 10.36. Found: C72.90, H 7.37, N 10.11.

EXAMPLE 87cis-1-(t-Butylacetamido)-3-(3-methoxyphenylureido)-5-phenyl-7-(4-tolyl)hexahydroazepin-2-one

Prepared fromcis-1-(t-butylacetamido)-3-amino-5-phenyl-7-(4-tolyl)hexahydroazepin-2-oneby a procedure analogous to that of Example 60 in 40% yield as anamorphous solid.

¹ H-NMR (δ, CDCl₃, TFA): 1.19 (singlet, 9H), 2.0-2.4 (multiplets, 4H),2.34 (s, 3H), 3.29 (m, 1H), 3.83 (s, 3H), 3.95 (AB_(q), J_(AB) =16,Δν=81, 2H), 5.22 (d, J=11, 1H), 5.40 (d, J=11, 1H), 6.8 and 7.1-7.4 (m,16H).

¹³ C-NMR (δ, CDCl₃, TFA): 22.0, 27.9, 38.6, 38.9, 45.6, 48.2, 52.7,55.5, 61.4, 71.2, 126.2, 126.6, 127.2, 128.9, 129.3, 130.0, 130.5,130.6, 133.4, 139.7, 143.9, 157.2, 169.4, 175.8.

IR (cm.⁻¹, KBr): 1660 (broad, C═O).

FAB MS (%): 557 (parent+1, 59), 484 (45), 408 (43), 250 (32), 207 (100),132 (33), 105 (43).

Anal. calc'd for C₃₃ H₄₀ N₄ O₄ •H₂ O: C 68.97, H 7.37, N 9.75. Found: C68.97, H 7.38, N 9.60.

EXAMPLE 88cis-1-(t-Butylacetamido)-3-(3-3-chlorophenylureido)-5-phenyl-7-(4-tolyl)hexahydroazepin-2-one

Prepared fromcis-1-(t-butylacetamido)-3-amino-5-phenyl-7-(4-tolyl)hexahydroazepin-2-oneby a procedure analogous to that of Example 60 in 41% yield as anamorphous solid.

¹ H-NMR (δ, CDCl₃, TFA): 1.20 (singlet, 9H), 2.0-2.4 (multiplets, 4H),2.34 (s, 3H), 3.29 (m, 1H), 3.94 (AB_(q), J_(AB) =16, Δν=58, 2H), 5.23(d, J=9, 1H), 5.42 (d, J=11, 1H), 7.1-7.5 (m, 16H).

¹³ C-NMR (δ, CDCl₃, TFA): 21.0, 27.9, 38.8, 38.9, 45.7, 48.2, 52.5,61.4, 64.6, 122.2, 125.7, 126.6, 127.2, 128.9, 129.3, 130.0, 130.5,133.5, 135.2, 137.4, 139.7, 144.0, 156.4, 169.3, 176.0.

IR (cm ⁻¹, KBr): 1660 (broad, C═O).

FAB MS (%): 561 (parent+1, 44), 488 (34), 408 (28), 207 (67), 157 (100).

Anal. calc'd for C₃₂ H₃₇ N₄ O₃ Cl•1/4H₂ O: C 67.95, H 6.68, N 9.91.Found: C 68.12, H 6.47, N 9.52.

EXAMPLE 89cis-1-(t-Butylacetamido)-3-(3-tolylureido)-5-phenyl-7-(3-tolyl)hexahydroazepin-2-one

Prepared fromcis-1-(t-butylacetamido)-3-amino-5-phenyl-7-(3-tolyl)hexahydroazepin-2-oneby a procedure analogous to that of Example 60 in 56% yield, M.P.252°-254° C.

¹ H-NMR (δ, CDCl₃, TFA): 1.20 (singlet, 9H), 2.0-2.4 (multiplets, 4H),2.32 (s, 3H), 2.33 (s, 3H), 3.27 (m, 1H), 3.93 (AB_(q), J_(AB) =16,Δν=54, 2H), 5.20 (d, J=9, 1H), 5.38 (d, J=11, 1H), 7.0-7.5 (m, 16H).

¹³ C-NMR (δ, CDCl₃, TFA): 21.1, 21.2, 28.0, 38.7, 39.0, 45.8, 48.3,52.6, 61.6, 120.4, 124.2, 126.4, 126.7, 127.2, 127.5, 128.9, 129.2,129.7, 130.1, 130.2, 135.3, 136.5, 139.2, 140.2, 144.0, 158, 169, 175.6.

IR (cm.⁻, KBr): 1660 (broad, C═O).

FAB MS (%): 541 (parent+1, 72), 468 (63), 408 (45), 250 (32), 207 (100),157 (100), 119 (68).

Anal. calc'd for C₃₃ H₄₀ N₄ O₃ : C 73.30, H 7.46, N 10.36. Found: C73.02, H 7.39, N 10.30.

EXAMPLE 90cis-1-(t-Butylacetamido)-3-(3-methoxyphenylureido)-5-phenyl-7-(3-tolyl)hexahydroazepin-2-one

Prepared fromcis-1-(t-butylacetamido)-3-amino-5-phenyl-7-(3-tolyl)hexahydroazepin-2-oneby a procedure analogous to that of Example 60 in 76.5% yield as anamorphous solid.

¹ H-NMR (δ, CDCl₃, TFA): 1.19 (singlet, 9H), 2.0-2.4 (multiplets, 4H),2.32 (s, 3H), 3.28 (m, 1H), 3.81 (s, 3H), 4.0 (m, 2H), 5.21 (d, J=9,1H), 5.39 (d, J=11, 1H), 6.7-6.9 and 7.1-7.4 (m, 16H).

¹³ C-NMR (δ, CDCl₃, TFA): 21.2, 28.0, 38.8, 39.1, 45.7, 48.2, 52.6,55.4, 61.6, 71.0, 126.4, 126.7, 127.2, 128.9, 129.2, 130.1, 130.5,136.6, 139.2, 144.1, 157, 169, 176.

IR (cm.⁻¹, KBr): 1660 (broad, C═O)

FAB MS (%): 557 (parent+1, 34), 484 (39), 408 (32), 207 (75), 119 (100),103 (100).

Anal. calc'd for C₃₃ H₄₀ N₄ O₄ •H₂ O: C 68.97, H 7.37, N 9.75. Found: C68.73, H 7.95 (-0.58), N 9.42.

EXAMPLE 91cis-1-(t-Butylacetamido)-3-(3-chlorophenylureido)-5-phenyl-7-(3-tolyl)hexahydroazepin-2-one

Prepared fromcis-1-(t-butylacetamido)-3-amino-5-phenyl-7-(3-tolyl)hexahydroazepin-2-oneby a procedure analogous to that of Example 60 in 65% yield as anamorphous solid.

¹ H-NMR (δ, CDCl₃, TFA): 1.20 (singlet, 9H), 2.0-2.4 (multiplets, 4H),2.33 (s, 3H), 3.29 (m, 1H), 3.95 (AB_(q), J_(AB) =16, Δν=58, 2H), 5.22(d, J=9, 1H), 5.44 (d, J=11, 1H), 7.1-7.4 (m, 16H).

¹³ C-NMR (δ, CDCl₃, TFA): 21.2, 28.0, 38.8, 39.0, 45.7, 48.2, 52.5,61.7, 71.1, 125.6, 126.3, 126.7, 127.2, 128.9, 129.2, 130.2, 130.5,135.2, 136.5, 139.2, 144.0, 157, 169, 176.

IR (cm.⁻¹, KBr): 1660 (broad, C═O).

FAB MS (%): 561 (parent+1, 30), 488 (75), 408 (43), 250 (37), 207 (100),115 (39).

Anal. calc'd for C₃₂ H₃₇ N₄ O₃ Cl•1/4H₂ O: C 67.95, H 6.68, N 9.91.Found: C 67.89, H 6.72, N 9.91.

EXAMPLE 921-(t-Butylacetamido)-3-(2-methylphenylureido)-5,7-diphenylhexahydroazepin-2-one

Prepared from the more polar amine diastereomer of1-(t-butylacetamido)-3-amino-5,7-diphenyl-hexahydroazepin-2-one inExample 60 in 26% yield, mp 145°-153° C.

¹ H-NMR (δ, CD₃ SOCD₃): 1.15 (singlet, 9H), 1.9-2.1 (m, 3H), 2.17 (s,3H), 2.61 (m, 1H), 3.25 (m, 1H), 3.51 (AB_(q), J_(AB) =16, Δν=214, 2H),5.10 (m, 1H), 5.30 (d, J=10, 1H), 6.8-7.4 (m, 15H), 7.77 (d, J=8, 1H),8.17 (s, 1H).

¹³ C-NMR (δ, CD₃ SOCD₃): 22.8, 28.5, 45.0, 47.0, 49.9, 51.8, 59.4, 67.3,120.9, 121.0, 122.0, 125.9, 126.0, 126.3, 126.7, 126.8, 127.2, 128.0,128.4, 128.5, 128.7, 129.4, 129.5, 130.1, 131.3, 138.2, 139.3, 146.3,154.4, 167.3, 173.4.

IR (cm ⁻¹, KBr): 1650 (broad, C═O)

FAB MS (%): 527 (parent+1, 90), 454 (75), 394 (45), 193 (100), 157 (67),119 (54), 91 (66).

Anal. Calc'd. for C₃₂ H₃₈ N₄ O₃ •1/2H₂ O: C 71.75, H 7.34, N 10.46.Found: C 71.84, H 7.10, N 10.27.

EXAMPLE 931-(t-Butylacetamido)-3-(4-chlorophenylureido)-5,7-diphenylhexahydroazepin-2-one

Prepared from the more polar amine diastereomer of1-(t-butylacetamido)-3-amino-5,7-diphenyl-hexahydroazepin-2-one inExample 60 in 19% yield, mp 165°-170° C.

¹ H-NMR (δ, CDCl₃, TFA): 1.18 (singlet, 9H), 2.03 (m, 1H), 2.2-2.4 (m,2H), 3.28 (m, 1H), 4.03 (AB_(q), J_(AB) =17, Dn=132, 2H), 5.26 (δ, J=9,1H), 5.43 (δ, J=11, 1H), 7.1-7.4 (m, 17H).

¹³ C-NMR (δ, CDCl₃, TFA): 27.7, 38.5, 38.6, 45.7, 48.1, 52.9, 53.7,61.9, 71.6, 124.7, 126.5, 127.3, 128.7, 128.9, 129.0, 129.4, 129.6,129.7, 129.8, 130.0, 133.6, 136.2, 143.6, 157.4, 169.8, 176.3.

IR (cm.⁻¹, KBr): 1650 (broad, C═O)

FAB MS (%): 547 (parent+1, 23), 474 (22), 420 (15), 394 (16), 193 (28),155 (45), 136 (30), 119 (100), 104 (40).

Anal. Calc'd. for C₃₁ H₃₅ N₄ O₃ Cl•1/2H₂ O: C 66.96, H 6.52, N 10.07.Found: C 66.65, H 6.33, N 9.86.

EXAMPLE 941-(t-Butylacetamido)-3-(5-(benztriazolyl)ureido)-5,7-diphenylhexahydroazepin-2-one

To a 35 mL round-bottomed flask equipped with N₂ inlet and condenserwere added 62 mg (0.382 mmol) benztriazole-5-carboxylic acid, 5 mL drytetrahydrofuran, 0.090 mL (0.420 mmol) diphenylphosphoryl azide, and0.060 mL (0.420 mmol) triethylamine. The reaction was refluxed for 1 hr,cooled briefly, and 150 mg (0.382 mmol) of1-(t-butylacetamido)-3-amino-5,7-diphenylhexahydroazepin-2-one (the morepolar amine diastereomer in Example 60) was added and refluxingcontinued for 14 hr. The reaction was cooled, filtered to remove a smallamount of amide byproduct that had formed, and the filtrate evaporated.The residue was triturated with chloroform to afford a white solid, 70mg (34%), mp 210°-220° C.

¹ H-NMR (δ, CDCl₃): 1.16 (singlet, 9H), 2.03 (m, 1H), 2.2-2.5 (m, 3H),3.18 (m, 1H), 3.28 (m, 1H), 4.01 (AB_(q), J_(AB) =16, Dn=108, 2H),5.2-5.3 (m, 2H), 5.64 (bs, 1H), 7.1-7.4 (m, 13H), 7.92 (d, J=9, 1H),8.06 (s, 1H), 8.38 (s, 1H).

¹³ C-NMR (δ, CDCl₃): 27.9, 38.6, 39.0, 45.6, 48.0, 52.5, 53.4, 61.8,116.1, 119.9, 125.2, 126.5, 127.4, 128.9, 129.5, 129.7, 129.9, 130.5,135.0, 136.3, 140.9, 143.7, 155.1, 163.0, 169.2, 175.8.

IR (cm.⁻¹, KBr): 1640 (broad, C═O)

FAB MS (%): 555 (parent+1, 64), 481 (70), 394 (35), 193 (83), 155 (55),119 (100).

HRMS: Calc'd. for C₃₁ H₃₆ N₇ O₃ : 554.2872. Found: 554.28607.

EXAMPLE 951-(t-Butylacetamido)-3-(3,4-dimethylphenylureido)-5,7-diphenylhexahydroazepin-2-one

Prepared as in Example 94, using the more polar isomer of1-(t-butylacetamido)-3-amino-5,7-diphenylhexahydroazepin-2-one describedin Example 60, in 48% yield, mp 185°-188° C.

¹ H-NMR (δ, CDCl₃): 1.19 (singlet, 9H), 2.0 (m, 1H), 2.14 (s, 3H), 2.15(s, 3H), 2.2-2.3 (m, 2H), 2.55 (m, 1H), 3.20 (m, 1H), 3.59 (AB_(q),J_(AB) =16, Dn=193, 2H), 5.16 (d, J=10, 1H), 5.24 (dd, J=7,10, 1H), 5.38(s, 1H), 6.71 (d, J=6, 1H), 7.0-7.4 (m, 13H), 7.53 (bs, 1H).

¹³ C-NMR (δ, CDCl₃): 19.0, 19.9, 28.6, 39.3, 39.4, 46.1, 48.2, 51.1,52.2, 61.2, 117.9, 121.8, 121.9, 126.5, 126.6, 127.0, 128.5, 128.6,128.8, 128.9, 129.4, 129.5, 130.0, 136.8, 137.1, 138.2, 145.3, 155.4,167.5, 175.0.

IR (cm.⁻¹, KBr): 1660 (broad, C═O).

FAB MS (%): 541 (48, parent+1), 468 (35), 394 (32), 309 (39), 193 (42),155 9100), 135 (72), 119 (100), 103 (96).

Anal. Calc'd. for C₃₃ H₄₀ N₄ O₃ : C 73.30, H 7.46, N 10.36. Found: C73.09, H 7.32, N 10.08.

EXAMPLE 961-(t-Butylacetamido)-3-(3-dimethylaminophenylureido)-5,7-diphenyl-hexahydroazepin-2-one

Prepared as in Example 94, using the more polar isomer of1-(t-butylacetamido)-3-amino-5,7-diphenyl-hexahydroazepin-2-onedescribed in Example 60, in 71% yield, mp 145°-153° C.

¹ H-NMR (δ, CDCl₃): 1.18 (singlet, 9H), 1.98 (m, 1H), 2.22 (m, 2H), 2.57(m, 1H), 2.87 (s, 6H), 3.20 (m, 1H), 3.58 (AB_(q), J_(AB) =16, Dn=174,2H), 5.17 (d, J=10, 1H), 5.26 (m, 1H), 5.42 (s, 1H), 6.3, 6.6, 6.7, 6.9,and 7.0-7.3 (m, 16H), 7.59 (s, 1H).

¹³ C-NMR (δ, CDCl₃): 28.6, 39.4, 39.5, 40.6, 46.0, 48.3, 51.1, 52.1,61.2, 104.5, 107.7, 108.5, 108.6, 126.6, 127.0, 128.6, 128.8, 128.9,129.1, 129.3, 129.5, 138.3, 140.1, 145.3, 151.5, 155.3, 167.5, 174.9.

IR (cm.⁻¹, KBr): 1640 (broad, C═O).

Anal. Calc'd. for C₃₃ H₄₁ N₅ O₃ •1/2H₂ O: C 70.19, H 7.50, N 12.40.Found: C 69.81, H 7.13, N 12.05.

The hydrochloride salt was formed using HCl in ether and crystallizedfrom acetone to afford a white solid, mp 190°-197° C.

Anal. Calc'd. for C₃₃ H₄₁ N₅ O₃.HCl: C 66.93, H 7.15, N 11.83. Found: C66.60, H 7.17, N 11.70.

EXAMPLE 97cis-1-(t-Butylacetamido)-3-(3-tolylureido)-5-phenyl-7-(3-methoxyphenyl)hexahydroazepin-2-one

Prepared from the more polar isomer of1-(t-butylacetamido)-3-amino-5-phenyl-7-(3-methoxyphenyl)hexahydroazepin-2-onein analogy with Example 60 in 40% yield, mp 245°-247° C.

¹ H-NMR (δ, CDCl₃, TFA): 1.19 (singlet, 9H), 1.9-2.4 (multiplets, 4H),2.33 (s, 3H), 3.28 (m, 1H), 3.81 (s, 3H), 3.97 (AB_(q), J_(AB) =17, DnYork=62, 2H), 5.23 (d, J=10, 1H), 5.38 (d, J=11, 1H), 6.8-7.4 (m, 16H).

¹³ C-NMR (δ, CDCl₃, TFA): 21.0, 27.9, 38.6, 38.8, 45.6, 48.2, 52.8,52.9, 55.5, 61.6, 114.7, 115.9, 121.9, 124.5, 126.6, 127.3, 128.0,128.9, 129.7, 130.5, 138.0, 140.3, 143.8, 158, 169, 175.6.

IR (cm.⁻¹, KBr): 1650 (broad, C═O)

FAB MS (%): 557 (parent+1, 30), 484 (45), 266 930), 223 (100), 132 (45),115 (42), 91 (44).

Anal. Calc'd. for C₃₃ H₄₀ N₄ O₄ : C 71.20, H 7.24, N 10.07. Found: C70.98, H 7.51, N 9.83.

EXAMPLE 98cis-1-(t-Butylacetamido)-3-(3-methoxyphenylureido)-5-phenyl-7-(3-methoxyphenyl)hexahydroazepin-2-one

Prepared from the more polar isomer of1-(t-butylacetamido)-3-amino-5-phenyl-7-(3-methoxyphenyl)hexahydroazepin-2-onein analogy with Example 60 in 46% yield as an amorphous solid.

¹ H-NMR (δ, CDCl₃, TFA): 1.19 (singlet, 9H), 2.0-2.4 (multiplets, 4H),3.29 (m, 1H), 3.80 (s, 3H), 3.82 (s, 3H), 3.8-3.9 and 4.0-4.1 (m, 2H),5.25 (m, 1H), 5.38 (m, 1H), 6.7-7.0 and 7.1-7.4 (m, 16H).

¹³ C-NMR (δ, CDCl₃, TFA): 22.1, 28.0, 38.7, 38.8, 45.6, 47, 52, 55.4,55.5, 61.5, 114.6, 115.8, 121.7, 126.6, 127.2, 128.9, 130.5, 143.9(remaining carbons not visible in this scan).

IR (cm.⁻¹, KBr): 1670, 1630, 1600 (broad, C═O).

FAB MS (%): 573 (parent+1, 45), 500 (52), 424 (35), 266 (34), 223 (100),132 (32), 115 (48), 91 (37).

Anal. Calc'd. for C₃₃ H₄₀ N₄ O₅ •H₂ O: C 67.10, H 7.17, N 9.48. Found: C67.01, H 7.23, N 9.20.

EXAMPLE 99cis-1-(t-Butylacetamido)-3-(3-chlorophenylureido)-5-phenyl-7-(3-methoxyphenyl)hexahydroazepin-2-one

Prepared from the more polar isomer of1-(t-butylacetamido)-3-amino-5-phenyl-7-(3-methoxyphenyl)hexahydroazepin-2-onein analogy with Example 60 in 31% yield as an amorphous solid.

¹ H-NMR (δ, CDCl₃, TFA): 1.20 (singlet, 9H), 2.0-2.4 (multiplets, 4H),2.33 (s, 3H), 3.29 (m, 1H), 3.81 (s, 3H), 3.96 (AB_(q), J_(AB) =17,Dn=59, 2H), 5.24 (d, J=9, 1H), 5.42 (d, J=11, 1H), 6.8-7.4 (m, 16H).

¹³ C-NMR (δ, CDCl₃, TFA): 22, 28.0, 38.7, 38.8, 45.6, 48.2, 52.5, 55.4,61.6, 114.7, 115.9, 121.8, 125.8, 126.6, 127.2, 128.9, 130.5, 130.6,138.1, 143.9, 156, 167, 175.

IR (cm.⁻¹, KBr): 1670, 1620 (broad, C═O).

FAB MS (%): 577 (parent+1, 35), 504 (46), 223 (100), 157 (73), 119 (51).

Anal. Calc'd. for C₃₂ H₃₇ N₄ O₄ Cl•H₂ O: C 64.58, H 6.60, N 9.41. Found:C 67.54, H 6.63, N 9.24.

EXAMPLE 100cis-1-(t-Butylacetamido)-3-(3-tolylureido)-5-phenyl-7-(4-trifluoromethylphenyl)hexahydroazepin-2-one

Prepared from the more polar isomer of1-(t-butylacetamido)-3-amino-5-phenyl-7-(4-trifluoromethylphenyl)hexahydroazepin-2-onein analogy with Example 60 in 10% yield as an amorphous solid.

¹ H-NMR (δ, CDCl₃, TFA): 1.19 (singlet, 9H), 2.0-2.4 (multiplets, 4H),2.34 (s, 3H), 3.31 (m, 1H), 3.82 (AB_(q), J_(AB) =16, Dn=36, 2H), 4.82and 5.02 (m, 1H), 5.3 (m, 1H), 7.0-7.7 (m, 16H).

¹³ C-NMR (δ, CDCl₃, TFA): 21.1, 28.0, 38.6, 38.8, 43.3, 45.6, 48.4,52.7, 61.0, 120.7, 121.2, 124.4, 125.0, 126.2, 126.5, 126.6, 126.9,127.3, 127.7, 128.2, 128.9, 129.7, 130.0, 131.5, 131.9, 134.8, 135.0,140.3, 140.5, 143.7, 143.9, 158, 168, 175.

IR (cm.⁻¹, KBr): 1680, 1660, 1640 (broad, C═O).

FAB MS (%): 595 (parent+1, 5), 482 (24), 349 (30), 157 (100), 135 (45),119 (99), 103 (51).

Anal. Calc'd. for C₃₃ H₃₇ N₄ O₃ F₃ •3/2H₂ O: C 63.75, H 6.49, N 9.01.Found: C 64.01, H 6.44, N 8.74.

EXAMPLE 101cis-1-(t-Butylacetamido)-3-(3-methoxyphenylureido)-5-phenyl-7-(4-trifluoromethylphenyl)hexahydroazepin-2-one

Prepared from the more polar isomer of1-(t-butylacetamido)-3-amino-5-phenyl-7-(4-trifluoromethylphenyl)hexahydroazepin-2-onein analogy with Example 60 in 48% yield as an amorphous solid.

¹ H-NMR (δ, CDCl₃, TFA): 1.18 (singlet, 9H), 2.0-2.4 (multiplets, 4H),3.31 (m, 1H), 3.82 (s, 3H), 3.83 (AB_(q), J_(Ab) =16, Dn=37, 2H), 4.82and 5.02 (m, 1H), 5.3-5.4 (m, 1H), 6.7-7.7 (m, 16H).

¹³ C-NMR (δ, CDCl₃, TFA): 22.1, 28.0, 38.5, 38.7, 43.3, 45.6, 48.4,55.5, 60.9, 126.2, 126.5, 126.6, 126.9, 127.3, 128.9, 130.1, 130.6,130.8, 140.5, 143.7, 144.0, 157, 168, 176.

IR (cm.⁻¹, KBr): 1660, 1640, 1600 (broad, C═O).

FAB MS (%): 611 (parent+1, 4), 498 (17), 349 (20), 157 (100).

Anal. Calc'd. for C₃₃ H₃₇ N₄ O₄ F₃ •H₂ O: C 63.05, H 6.25, N 8.91.Found: C 63.05, H 6.11, N 8.59.

EXAMPLE 102cis-1-(t-Butylacetamido)-3-(3-chlorophenylureido)-5-phenyl-7-(4-trifluoromethylphenyl)hexahydroazepin-2-one

Prepared from the more polar isomer of1-(t-butylacetamido)-3-amino-5-phenyl-7-(4-trifluoromethylphenyl)hexahydroazepin-2-onein analogy with Example 60 in 34% yield as an amorphous solid.

¹ H-NMR (δ, CDCl₃, TFA): 1.19 (singlet, 9H), 2.0-2.4 (multiplets, 4H),3.33 (m, 1H), 3.93 (AB_(q), J_(AB) =17, Dn=89, 2H), 5.37 (m, 1H), 5.46(d, J=11, 1H), 7.0-7.7 (m, 16H).

¹³ C-NMR (δ, CDCl₃, TFA): 27.8, 38.6, 38.7, 45.6, 48.3, 52.6, 53.1,61.1, 120.4, 122.6, 126.2, 126.6, 127.4, 129.0, 130.0, 130.6, 132.0,135.3, 137.0, 140.3, 143.6, 157, 169, 176.1.

IR (cm.⁻¹, KBr): 1680, 1640 (broad, C═O).

FAB MS (%): 615 (parent+1, 6), 233 (23), 157 (100), 135 (47), 119 (99),103 (52).

Anal. Calc'd. for C₃₂ H₃₄ N₄ O₃ ClF₃.5/4H₂ O: C 60.28, H 5.77, N 8.79.Found: C 60.17, H 5.91, N 8.64.

EXAMPLE 103cis-1-(t-Butylacetamido)-3-(3-tolylureido)-5-phenyl-7-(3-fluorophenyl)hexahydroazepin-2-one

Prepared from the more polar isomer of1-(t-butylacetamido)-3-amino-5-phenyl-7-(3-fluorophenyl)hexahydroazepin-2-onein analogy with Example 60 in 39% yield as an amorphous solid.

¹ H-NMR (δ, CDCl₃, TFA): 1.22 (singlet, 9H), 2.0-2.4 (multiplets, 4H),2.33 (s, 3H), 3.28 (m, 1H), 3.87 (AB_(q), J_(AB) =16, Dn=43, 2H), 5.21(d, J=9, 1H), 5.32 (d, J=11, 1H), 7.0-7.4 (m, 16H).

¹³ C-NMR (δ, CDCl₃, TFA): 21.2, 28.1, 38.8, 38.9, 45.7, 48.3, 52.6,60.8, 126.7, 127.3, 128.9, 129.6, 144.0, 157, 167, 175 (not all carbonsvisible in this scan).

IR (cm.⁻¹, KBr): 1660, 1640 (broad, C═O).

FAB MS (%): 545 (parent+1, 62), 472 (52), 211 (76), 157 (100), 132 (53),107 (53), 91 (57).

Anal. Calc'd. for C₃₂ H₃₇ N₄ O₃ F•3/4H₂ O: C 68.86, H 6.95, N 10.04.Found: C 68.87, H 6.83, N 9.73.

EXAMPLE 104cis-1-(t-Butylacetamido)-3-(3-methoxyphenylureido)-5-phenyl-7-(3-fluorophenyl)hexahydroazepin-2-one

Prepared from the more polar isomer of1-(t-butylacetamido)-3-amino-5-phenyl-7-(3-fluorophenyl)hexahydroazepin-2-onein analogy with Example 60 in 30% yield as an amorphous solid.

¹ H-NMR (δ, CDCl₃, TFA): 1.20 (singlet, 9H), 2.0-2.4 (multiplets, 4H),3.28 (m, 1H), 3.80 (s, 3H), 3.9 (m, 2H), 5.23 (d, J=11, 1H), 5.34 (d,J=11, 1H), 6.7-6.9 and 7.1-7.4 (m, 16H).

¹³ C-NMR (δ, CDCl₃, TFA): 22.2, 28.2, 38.8, 38.9, 45.7, 48.3, 52.5,55.4, 60.8, 116.5, 126.7, 127.2, 128.9, 143.9, 176 (not all carbonsvisible in this scan).

IR (cm.⁻¹, KBr): 1670, 1640 (broad, C═O).

FAB MS (%): 561 (parent+1, 95), 488 (78), 211 (100), 157 (89), 119 (88).

Anal. Calc'd. for C₃₂ H₃₇ N₄ O₄ F•1/2H₂ O: C 67.47, H 6.72, N 9.83.Found: C 67.20, H 6.70, N 9.14 (-0.69).

HRMS Calc'd. for C₃₇ C₃₇ N₄ O₄ F: 561.2868. Found: 561.28552.

EXAMPLE 105cis-1-(t-Butylacetamido)-3-(3-chlorophenylureido)-5-phenyl-7-(3-fluorophenyl)hexahydroazepin-2-one

Prepared from the more polar isomer of1-(t-butylacetamido)-3-amino-5-phenyl-7-(3-fluorophenyl)hexahydroazepin-2-onein analogy with Example 60 in 52% yield as an amorphous solid.

¹ H-NMR (δ, CDCl₃, TFA): 1.22 (singlet, 9H), 2.0-2.4 (multiplets, 4H),2.33 (s, 3H), 3.29 (m, 1H), 3.9 (m, 2H), 5.26 (d, J=11, 1H), 5.42 (m,1H), 6.9-7.3 (m, 16H).

¹³ C-NMR (δ, CDCl₃, TFA): 22.2, 28.1, 38.8, 39.0, 45.6, 48.4, 52.5,60.9, 116.6, 125.1, 125.4, 126.6, 126.7, 127.3, 128.9, 130.5, 130.9,131.0, 135.2, 143.9, 157, 164, 175.

IR (cm.⁻¹, KBr): 1670, 1640 (broad, C═O).

FAB MS (%): 565 (parent+1, 58), 492 (71), 211 (100), 157 (91), 132 (53(,115 (42), 91 (49).

Anal. Calc'd. for C₃₁ H₃₄ N₄ O₃ ClF•1/2H₂ O: C 64.86, H 6.14, N 9.76.Found: C 64.79, H 5.93, N 9.42.

EXAMPLE 106 1-(t-Butylacetamido)-3-(3-methyl,4-chlorophenylureido)-5,7-diphenylhexahydroazepin-2-one

Prepared from the more polar isomer of1-(t-butylacetamido)-3-amino-5,7-phenyl-hexahydroazepin-2-one in Example60 in analogy with the procedure given in Example 94 in 70% yield, mp168°-171° C.

¹ H-NMR (δ, CDCl₃): 1.19 (singlet, 9H), 2.0-2.3 (m, 3H), 2.24 (s, 3H),2.62 (m, 1H), 3.17 (m, 1H), 3.58 (AB_(q), J_(AB) =16, Dn=212, 2H), 5.18(d, J=11, 1H), 5.2 (m, 1H), 6.87 (d, J=7, 1H), 7.0-7.4 (m, 15H), 8.03(bs, 1H).

¹³ C-NMR (δ, CDCl₃): 20.1, 28.6, 38.3, 40.0, 46.3, 48.2, 51.3, 52.4,61.2, 118.3, 126.6, 126.9, 127.1, 127.4, 128.6, 128.7, 128.9, 129.0,129.2, 129.3 , 129 . 4, 129.5, 136.3, 138.3, 138.4, 145.2, 155.4, 167.6,175.4.

IR (cm.⁻¹, KBr): 1660, 1640 (broad, C═O)

FAB MS (%): 561 (parent+1, 22), 488 (37), 394 (30), 193 (100), 132 (40),119 (47), 115 (43), 91 (62).

Anal. Calc'd. for C₃₂ H₃₇ N₄ O₃ Cl•1/2H₂ O: C 67.41, H 6.72, N 9.83.Found: C 67.41, H 6.73, N 9.76.

EXAMPLE 1071-(t-Butylacetamido)-3-(3-nitrophenylureido)-5,7-diphenylhexahydroazepin-2-one

Prepared from the more polar isomer of1-(t-butylacetamido)-3-amino-5,7-phenyl-hexahydroazepin-2-one in Example60 in 64% yield, mp 182°-185° C.

¹ H-NMR (δ, CD₃ SOCD₃): 1.15 (singlet, 9H), 1.9-2.1 (m, 3H), 2.63 (m,1H), 3.3 (m, 1H), 3.52 (AB_(q), J_(AB) =16, Dn=228, 2H), 5.13 (m, 1H),5.32 (d, J=11, 1H), 6.9-7.7 (m, 15H), 8.54 (s, 1H), 9.56 (s, 1H).

¹³ C-NMR (δ, CD₃ SOCD₃): 28.5, 44.9, 47.0, 50.0, 51.6, 59.4, 126.4,126.8, 128.5, 128.7, 129.4, 139.2, 141.8, 146.2, 148.2, 153 . 8, 167.2 ,173.1.

IR (cm.⁻¹, KBr): 1660, 1640 (broad, C═O).

FAB MS (%): 558 (parent+1, 20), 485 (23), 193 (67), 155 (52), 185 (85),119 (100), 103 (48), 91 (39).

Anal. Calc'd. for C₃₁ H₃₅ N₅ O₅ •2/3H₂ O: C 65.36, H 6.43, N 12.29.Found: C 65.06, H 6.35, N 11.91.

EXAMPLE 1081-(t-Butylacetamido)-3-(3-aminophenylureido)-5,7-diphenylhexahydroazepin-2-one

Prepared from1-(t-butylacetamido)-3-(3-aminophenylureido)-5,7-diphenylhexahydroazepin-2-onein 90% yield by reduction with 5 equivalents of ammonium formate inethanol at room temperature in the presence of 10% palladium-on-carbon,mp 163°-168° C.

¹ H-NMR (δ, CDCl₃): 1.17 (singlet, 9H), 2.0-2.3 (m, 3H), 2.48 (m, 1H),3.18 (m, 1H), 3.59 (AB_(q), J_(AB) =16, Dn=160, 2H), 4.08 (bs, 2H), 5.15(d, J=10, 1H), 5.21 (m, 1H), 5.47 (s, 1H), 6.26 (d, J=7, 1H), 6.7-7.4(m, 15H), 8.96 (bs, 1H).

¹³ C-NMR (δ, CDCl₃): 28.6, 39.0, 39.6, 46.1, 48.2, 51.2, 52.2, 60.4,61.1, 106.5, 109.7, 126.6, 126.9, 127.0, 128.4, 128.6, 128.8, 128.9,129.1, 129.5, 129.7, 138.3, 140.4, 145.3, 147.3, 155.4, 167.6, 175.1.

IR (cm.⁻¹, KBr): 1640 (broad, C═O).

FAB MS (%): 528 (parent+1, 81), 455 (53), 394 (69), 193 (94), 157 (99),119 (100).

Anal. Calc'd. for C₃₁ H₃₇ N₅ O₃ Cl•H₂ O: C 68.23, H 7.20, N 12.83.Found: C 68.73 (+0.50), H 7.07, N 12.43.

EXAMPLE 1091-(t-Butylacetamido)-3-(3-acetylaminophenylureido)-5,7-diphenylhexahydroazepin-2-one

Prepared from1-(t-butylacetamido)-3-(3-aminophenylureido)-5,7-diphenylhexahydroazepin-2-one70% yield by acetylation with acetic anhydride in pyridine at reflux for14 hr, mp 195°-205° C.

¹ H-NMR (δ, CD₃ SOCD₃): 1.15 (singlet, 9H), 1.8-2.0 (m, 3H), 2.57 (m,1H), 3.17 (m, 1H), 3.51 (AB_(q), J_(AB) =16, Dn=228, 2H), 5.01 (m, 1H),5.30 (d, J=10, 1H), 6.7-7.4 (m, 15H), 7.67 (s, 1H), 9.01 (s, 1H), 9.82(bs, 1H).

¹³ C-NMR (δ, CD₃ SOCD₃): 24.0, 28.5, 45.1, 47.0, 49.9, 51.6, 59.4,112.0, 112.3, 126.3, 126.8, 128.0, 128.1, 128.5, 128.7, 128.8, 129.3,129.4, 129.5, 134.6, 139.3, 139.7, 140.8, 146.3, 154.1, 167.3, 168.2,173.3.

IR (cm.⁻¹, KBr): 1660, 1640 (broad, C═O).

FAB MS (%): 570 (parent+1, 25), 497 (29), 193 (42), 157 (100), 119 (34).

Anal. Calc'd. for C₃₃ H₃₉ N₅ O₄.H₂ O: C 67.44, H 7.03, N 11.92. Found: C67.31, H 7.08, N 11.71.

EXAMPLE 1101-(t-Butylacetamido)-3-(3-methylsulfonylaminophenylureido)-5,7-diphenylhexahydroazepin-2-one

Prepared from1-(t-butylacetamido)-3-(3-aminophenylureido)-5,7-diphenylhexahydroazepin-2-onein 69% yield by reaction with methanesulfonyl chloride in pyridine atroom temperature, mp 185°-192° C.

¹ H-NMR (δ, CD₃ SOCD₃): 1.15 (singlet, 9H), 1.8-2.0 (m, 3H), 2.57 (m,1H), 2.94 (s, 3H), 3.20 (m, 1H), 3.50 (AB_(q), J_(AB) =16, Dn=231, 2H),5.09 (d, J=11, 1H), 5.30 (d, J=10, 1H), 6.6-7.4 (m, 16H), 9.11 (s, 1H),9.62 (s, 3H).

¹³ C-NMR (δ, CD₃ SOCD₃): 28.5, 45.0, 47.0, 49.9, 51.5, 59.4, 108.3,126.8, 126.9, 128.0, 128.4, 128.5, 128.6, 128.7, 129.3, 129.4, 129.5,129.6, 139.3, 141.4, 146.3, 153.6, 167.3, 173.2.

IR (cm.⁻¹, KBr): 1640 (broad, C═O).

FAB MS (%): 606 (parent+1, 47), 533 (64), 193 (100), 119 (63), 91 (59).

Anal. Calc'd. for C₃₂ H₃₉ N₅ O₅ S•1/2H₂ O: C 62.52, H 6.56, N 11.39, S5.22. Found: C 62.12, H 6.80, N 11.08, S 5.32.

EXAMPLE 1111-(t-Butylacetamido)-3-(3-(N-methylureido)phenylureido)-5,7-diphenylhexahydroazepin-2-one

Prepared from1-(t-butylacetamido)-3-(3-aminophenylureido)-5,7-diphenylhexahydroazepin-2-onein 45% yield by reaction with methylisocyanate in refluxingtetrahydrofuran for 18 hr, mp 185°-195° C.

¹ H-NMR (δ, CDCl₃): 1.10 (singlet, 9H), 1.9-2.2 (m, 3H), 2.5 (m, 1H),2.60 (bs, 3H), 3.04 and 3.8 (multiplets, 2H), 3.28 (m, 1H), 5.0-5.2(broad multiplet, 2H), 5.4-5.6 (broad multiplet, 2H), 6.8-7.4 (m, 15H),7.6 (bs, 1H), 8.1 (bs, 1H).

¹³ C-NMR (δ, CDCl₃): 26.6, 28.5, 46.0, 51.1, 126.9, 127.0, 128.4, 128.6,128.7, 128.8, 128.9, 129.0, 129.5, 129.6, remaining carbons not visiblein this scan.

IR (cm.⁻¹, KBr): 1640 (broad, C═O).

FAB MS (%): 585 (parent+1, 26), 512 (60), 193 (100), 115 (42), 91 (58).

Anal. Calc'd. for C₃₃ H₄₀ N₆ O₄ •H₂ O: C 65.76, H 7.02, N 13.94. Found:C 65.94, H 6.74, N 13.58.

EXAMPLE 112 N-(1-Methylcyclohexyl)2-[3-bromo-2-oxo-5-(phenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared in analogy with Example 1 using N-(1-methylcyclohexyl)iodoacetamide to alkylate3-bromo-2-oxo-5-(phenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepine in 75%yield, mp 164°-168° C.

¹ H-NMR (δ, CDCl₃): 1.35 (s, 9H), 1.46 (s, 3H), 1.2-1.5 and 1.9-2.1 (m,10H), 2.62 and 2.79 (multiplets for 2 diastereomers, 1H), 2.92 (m, 1H),4.2-4.7 (m, 4H), 6.0 and 6.11 (singlets, 1H), 6.6-7.4 (m, 9H).

¹³ C-NMR (δ, CDCl₃): 121.9, 22.0, 25.5, 26.4, 36.3, 36.9, 43.0, 43.1,44.1, 44.8, 47.1, 53.7, 54.8, 55.1, 56.5, 123.2, 127.5, 127.6, 127.7,127.8, 128.0, 128.1, 128.7, 128.8, 129.0, 137.5, 137.7, 139.0, 140.7,141.1, 167.1, 168.2, 168.7.

IR (cm-⁻¹, KBr): 1660 broad (C═O).

MS (%): 468/470 (parent for Br⁷⁹ /Br⁸¹, 1/1), 276 (50), 250 (51), 165(40), 97 (38), 55 (100).

N-(1-Methylcyclohexyl)2-[3-azido-2-oxo-5-(phenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared in analogy with Example 1 in 41% yield as an oil.

¹ H-NMR (δ, CDCl₃): 1.29 (s, 9H), 1.43 (s, 3H), 1.1-1.6 and 1.8-2.0 (m,10H), 2.76 (m, 1H), 2.92 (m, 1H), 3.09 (AB_(q), J_(AB) =15, dn=317, 2H),3.97 (m, 1H), 4.20 (m, 1H), 6.18 (bs, 1H), 6.9-7.5 (m, 9H).

¹³ C-NMR (δ, CDCl₃)): 21.8, 22.0, 25.5, 26.4, 35.7, 35.8, 36.0, 36.1,36.3, 36.9, 37.0, 43.7, 53.4, 54.7, 58.4, 125.5, 125.6, 125.7, 125.8,125.9, 126.0, 126.2, 126.5, 126.6, 126.7, 127.3, 127.5, 127.6, 127.7,128.0, 128.5, 128.7, 129.2, 129.3, 130.3, 130.4, 1307.9, 141.0, 141.1,168.0, 170.0.

IR (cm.⁻¹, KBr): 2100 (N₃) and 1675 broad (C═O).

FAB MS (%): 432 (parent+1, 32), 406 (70), 319 (100), 293 (92), 194 (90),91 (92).

HRMS Calc'd. for C₂₅ H₂₉ N₅ O₂ : 431.2315. Found: 431.23135.

N-(1-Methylcyclohexyl)2-[3-amino-2-oxo-5-(phenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared in analogy with Example 1 in 69% yield as a white foam.

¹ H-NMR (δ, CDCl₃): 1.26 (s, 9H), 1.39 (s, 3H), 1.0-1.7 and 1.8-2.0 (m,10H), 2.22 (bs, 2H), NH2), 2.5 (m, 1H), 2.78 (m, 1H), 3.08 (AB_(q),J_(AB) =15, dn=305, 2H), 3.48 (m, 1H), 4.10 (m, 1H), 6.10 (bs, 1H),6.9-7.4 (m, 9H).

¹³ C-NMR (δ, CDCl₃): 21.9, 25.5, 26.4, 31.5, 36.2, 36.8, 39.7, 44.5,50.7, 53.4, 54.4, 125.3, 125.4, 125.5, 126.2, 127.2, 128.3, 128.5,128.8, 130.2, 138.7, 141.6, 141.8, 168.3, 175.1.

IR (cm.⁻¹, KBr): 1660 broad (C═O).

FAB MS (%): 406 (parent+1, 84), 293 (100), 237 (38), 194 (43).

HRMS Calc'd. for C₂₅ H₃₁ N₃ O₂ : 405.2409. Found: 405.23807.

N-(1-Methylcyclohexyl)2-[3-(3-(3-ethylphenyl)ureido)-2-oxo-5-(phenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared from N-(1-methylcyclohexyl)2-[3-amino-2-oxo-5-(phenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide as in Example 1, mp 130°-140° C., 94% yield.

¹ H-NMR (δ, CDCl₃): 1.16 (t, J=8, 3H),1.28 (s, 9H), 1.37 (s, 3H),1.2-1.5 (m, 6H), 1.8-2.0 (m, 4H), 2.54 (q, J=8, 2H), 2.9 and 3.1 (m,2H), 3.24 (AB_(q), J_(AB) =16, dn=297, 2H), 4.22 (d, J=8, 1H), 4.66 (m,1H), 5.90 (bs, 1H), 6.5-7.4 (m, 13H), 7.71 (bs, 1H).

¹³ C-NMR (δ, CDCl₃): 15.6, 21.9, 22.0, 25.4, 26.1, 28.9, 36.4, 36.6,37.3, 44.4, 50.1, 53.8, 54.0, 117.2, 119.6, 119.7, 122.5, 124.9, 125.0,126.3, 126.4, 127.8, 127.9, 128.4, 128.8, 128.9, 129.0, 130.7, 130.8,138.3, 139.1, 141.2 , 141.8, 145.3, 155.4, 167.7, 173.0.

IR (cm.⁻¹, KBr): 1650 broad (C═O).

FAB MS (%): 553 (parent+1, 32), 440 (68), 293 (84), 220 (82), 194 (100),91 (56).

Anal. Calc'd. for C₃₄ H₄₀ N₄ O₃.1/4H₂ O: C 73.29, H 7.33, N 10.05.Found: C 73.30, H 7.15, N 10.25.

EXAMPLE 113 N-(1-Methylcyclohexyl)2-[3-(3-(3-chlorophenyl)ureido)-2-oxo-5-(phenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared from N-(1-methylcyclohexyl)2-[3-amino-2-oxo-5-(phenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide as in Example 107, mp 215°-220° C., 84% yield.

¹ H-NMR (δ, CDCl₃): 1.28 (s, 9H), 1.36 (s, 3H), 1.2-1.5 (m, 6H), 1.8-2.0(m, 4H), 2.9-3.0 (m, 2H), 3.33 (AB_(q), J_(AB) =16, dn=284, 2H), 4.26(d, J=7, 1H), 4.63 (m, 1H), 5.79 (bs, 1H), 6.6-7.6 (m, 13H), 7.99 (bs,1H).

¹³ C-NMR (δ, CDCl₃): 22.0, 22.1, 25.4, 25.9, 36.4, 36.7, 36.9, 44.5,53.4, 54.1, 117.1, 119.1, 122.2, 124.4, 124.5, 126.3, 126.5, 126.6,127.8, 128.4, 129.1, 129.6, 130.8, 134.3, 138.2, 140.7, 141.1, 141.7,155.1, 167.4, 173.2.

IR (cm.⁻¹, KBr): 1650 broad (C═O)

FAB MS (%): 559/561 (parent+1, Cl³⁵ /Cl³⁷ 21/8), 446 (69), 293 (55), 237(58), 220 (92), 194 (100), 97 (80).

Anal. Calc'd. for C₃₂ H₃₅ N₄ O₃ Cl: C 68.74, H 6.31, N 10.02. Found: C68.40, H 6.19, N 9.82.

EXAMPLE 114 N-(1-Methylcyclohexyl)2-[3-(3-(3-tolyl)ureido)-2-oxo-5-(phenyl)-2,3,4,5-tetra-hydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared from N-(1-methylcyclohexyl)2-[3-amino-2-oxo-5-(phenyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide as in Example 107, mp 220°-225° C., 85% yield.

¹ H-NMR (δ, CDCl₃): 1.28 (s, 9H), 1.38 (s, 3H), 1.2-1.5 (m, 6H), 1.8-2.0(m, 4H), 2.23 (s, 3H), 2.8 (m, 1H), 3.06 (m, 1H), 3.22 (AB_(q), J_(AB)=16, Δν=297, 2H), 4.23 (d, J=8, 1H), 4.65 (m, 1H), 5.90 (bs, 1H),6.5-7.4 (m, 13H), 7.68 (bs, 1H).

¹³ C-NMR (δ, CDCl₃): 21.5, 21.9, 22.0, 25.5, 26.1, 36.4, 37.2, 44.4,50.1, 53.8, 53.9, 116.9, 117.0, 120.6, 123.7, 124.9, 126.3, 126.5,127.8, 128.3, 128.5, 128.7, 129.0, 129.1, 130.7, 130.8, 138.3, 138.8,139.0, 141.2, 141.8, 155.3, 167.6, 172.9.

IR (cm.⁻¹, KBr): 1650 broad (C═O).

FAB MS (%): 539 (parent+1, 60), 426 (82), 293 (92), 220 (94), 194 (100),119 (73), 97 (71), 91 (99).

EXAMPLE 115 2-(Cyclohexyl)-2-phenylethanol

To a 500 mL round-bottomed flask equipped with condenser and N₂ inletwere added 15 g (68.8 mmol) α-phenylcyclohexylacetic acid, 110 mL drytetrahydrofuran, and 137 mL (275 mmol) of a 2M solution of borane-methylsulfide in tetrahydrofuran. The solution was refluxed 60 hr, cooled, andevaporated. The residue was taken up carefully in 200 mL ethanol,treated with 2 g sodium carbonate, and refluxed 3 hr. The reaction wascooled, evaporated, taken up in ethyl acetate/water, separated, and theaqueous phase extracted with fresh ethyl acetate. The organic layerswere combined, washed with brine, dried over sodium sulfate, andevaporated to an oil which solidified on standing. The yield was 12.27 g(87%).

¹ H-NMR (δ, CDCl₃): 0.7-1.9 (m, 11H), 2.54 (m, 1H), 3.7-3.9 (m, 2H),7.1-7.3 (m, 5H).

2-(Cyclohexyl)-2-phenylethanol tosylate

To a 125 mL round-bottomed flask were added 12.27 g (60.15 mmol)2-(cyclohexyl)-2-phenylethanol and 30 mL dry pyridine. The reaction wascooled to 0° C., and 13.78 g (72.18 mmol) tosyl chloride added. Thereaction was let stand at 0° C. for 14 hr, poured into water, andextracted into ether. The ether layer was washed with 3 portions of 1Nhydrochloric acid, 3 portions of saturated aqueous sodium bicarbonatesolution, 2 portions water, and brine, dried over sodium sulfate, andevaporated. The residue was slurried in ethanol and collected byfiltration to afford a white solid, mp 95°-100° C. 13 1 g (61%)

¹ H-NMR (δ, CDCl₃): 0.6-1.7 (m, 11H), 2.40 (s, 3H), 2.64 (m, 1H),4.1-4.3 (m, 2H), 6.9-7.5 (m, 5H).

IR (cm.⁻¹, KBr): 2940 (C--H) and 1600 (C═C).

MS (%): 186 (100, parent for elimination of tosic acid), 104 (95), 91(70).

Anal. Calc'd. for C₂₁ H₂₆ O₃ S: C 70.35, H 7.31. Found: C 70.32, H 7.33.

2-(Cyclohexyl)-2-phenyl-1-iodoethane

To a 250 mL round-bottomed flask equipped with condenser and N₂ inletwere added 13.9 g (39.4 mmol) 2-(cyclohexyl)-2-phenylethanol tosylate,80 mL acetone and 6.49 g (43.3 mmol) sodium iodide. The reaction wasrefluxed 36 hr, cooled, and evaporated. The residue was taken up inethyl acetate, washed with water and aqueous sodium bisulfite solution,dried over sodium sulfate, and evaporated to an oil, 12.11 g (98%),which was used directly in the next step.

¹ H-NMR (δ, CDCl₃): 0.7-1.9 (m, 11H), 2.60 (m, 1H), 3.4 and 3.6 (m, 2H),7.0-7.3 (m, 5H).

Diethyl-(2-(cyclohexyl)-2-phenylethyl)malonate

To a 500 mL round-bottomed flask equipped with condenser and N₂ inletwere added 3.05 g (77.1 mmol) sodium hydride, which was washed withhexane and the hexane pipetted off, and 100 mL dry tetrahydrofuran. Tothe stirring suspension was added a solution of 12.34 g (77.1 mmol)diethyl malonate in 50 mL dry tetrahydrofuran dropwise over 30 min. Oncegas evolution had ceased, a solution of 12.11 g (38.57mmol)2-(cyclohexyl)-2-phenyl-1-iodoethane in 40 mL dry tetrahydrofuran wasadded, and the reaction refluxed 3 days. The reaction was concentrated,poured into 1N hydrochloric acid, and extracted twice into ethylacetate. The combined organic layer was washed with water, 3 portions ofaqueous sodium bisulfite solution, and brine, dried over sodium sulfate,and evaporated. The residue was chromatographed on silica gel usinghexane/ethyl acetate as eluant to afford an oil, 12.53 g (87%).

¹ H-NMR (δ, CDCl₃): 0.6-2.0 (m, 12H), 1.12 (t, J=7, 3H), 1.20 (t, J=7,3H), 2.24 (m, 1H), 2.32 (m, 1H), 2.95 (dd, J=4,10, 1H), 3.98 (m, 2H),4.15 (m, 2H), 6.9-7.2 (m, 5H).

¹³ C-NMR (δ, CDCl₃): 13.9, 14.1, 26.4, 26.5, 31.1, 31.2, 32.0, 43.3,49.7, 50.3, 61.0, 61.2, 126.3, 128.2, 128.5, 142.6, 169.4, 169.6.

IR (cm.⁻¹, KBr): 1738 (C═O).

MS (%): 346 (parent, 12), 160 (100), 114 (60), 28 (59).

HRMS Calc'd. for C₂₁ H₃₀ O₄ : 346.2136. Found: 346.21838.

3-Cyclohexyl-3-phenylbutanoic acid

To a 250 mL round-bottomed flask equipped with condenser and N₂ inletwere added 12.53 g (36.2 mmol)diethyl-(2-(cyclohexyl)-2-phenylethyl)malonate, 80 mL acetic acid, and25 mL 6N hydrochloric acid. The reaction was refluxed 20 hr, cooled,poured into water, and extracted into ethyl acetate. The organic phasewas washed with water and brine, dried over sodium sulfate, andevaporated. Evaporation from heptane removed traces of water to affordan oil, 9.78 g (99% crude yield).

¹ H-NMR (δ, CDCl₃): 0.8-2.3 (m, 16H), 7.0-7.3 (m, 5H).

¹³ C-NMR (δ, CDCl₃): 26.5, 27.7, 31.2, 31.3, 32.6, 43.2, 51.6, 126.2,128.3, 128.5, 143.3, 180.8.

IR (cm.⁻¹, KBr): 1720 (C═O)

MS (%): 246 (parent, 13), 173 (45), 163 (52), 117 (78), 104 (100), 91(79), 55 (48).

HRMS Calc'd. for C₁₆ H₂₂ O₂ : 246.1614. Found: 246.15968.

The remaining steps were carried out as described for the analogouscompounds in Example 22:

4-Cyclohexyl-1,2,3,4-tetrahydronaphth-1-one

Prepared as an oil in 74% yield.

¹ H-NMR (δ, CDCl₃): 1.9-2.1 (m, 5H), 1.4-1.8 (m, 6H), 2.0-2.2 (m, 2H),2.4-2.7 (m, 3H), 7.0-7.3 (m, 3H), 7.88 (m, 1H).

¹³ C-NMR (δ, CDCl₃): 24.3, 26.3, 26.5, 30.5, 35.0, 39.9, 44.0, 126.6,127.4, 129.2, 132.3, 132.6, 147.3, 198.6.

IR (cm.⁻¹, KBr): 1690 (C═O)

MS (%): 228 (parent, 7), 146 (100), 55 (20).

HRMS Calc'd. for C₁₆ H₂₀ O: 228.1509. Found: 228.15016.

4-Cyclohexyl-1,2,3,4-tetrahydronaphth-1-one oxime

Prepared as a solid, mp 120°-123° C. in 71% yield.

¹ H-NMR (δ, CDCl₃): 0.8-1.7 (m, 11H), 1.88 (m, 1H), 2.12 (m, 1H), 2.39(m, 1H), 2.79 (m, 2H), 7.0-7.3 (m, 3H), 7.77 (m, 1H).

¹³ C-NMR (δ, CDCl₃): 20.5, 22.4, 26.3, 26.4, 31.0, 32.0, 38.8, 44.9,124.6, 126.6, 128.5, 129.7, 129.9, 143.2, 155.6.

IR (cm.⁻¹, KBr): 1640 (weak) (C═N).

Anal. Calc'd. for C₁₆ H₂₁ NO: C 78.97, H 8.70, N 5.75. Found: C 78.83, H8.74, N 5.64.

5-Cyclohexyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one

Prepared as a white solid, mp 125°-128° C., in 80% yield.

¹ H-NMR (δ, CDCl₃): 0.6-2.0 (m, 12H), 2.2-2.4 (m, 3H), 2.59 (m, 1H),6.9-7.2 (m, 4H), 8.80 (bs, 1H).

¹³ C-NMR (δ, CDCl₃): 26.3, 26.4, 31.0, 31.6, 32.5, 32.7, 38.7, 45.8,122.4, 125.3, 126.9, 128.6, 136.3, 138.2, 176.1.

IR (cm.⁻¹, KBr): 1680 (C═O)

MS (%): 243 (40, parent), 160 (100), 132 (32), 118 (37).

Anal. Calc'd. for C₁₆ H₂₁ NO: C 78.97, H 8.70, N 5.75. Found: C 78.77, H8.71, N 5.66.

3-Bromo-5-cyclohexyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one

Prepared as a white solid, mp 104°-107° C. in 54% yield.

¹ H-NMR (δ, CDCl₃): 0.6-2.0 (m, 11H), 2.25 (m, 1H), 2.69 (m, 2H), 4.37(dd, J=7,11, 1H), 7.0-7.3 (m, 4H), 8.90 (bs, 1H).

¹³ C-NMR (δ, CDCl₃): 26.1, 26.4, 30.3, 32.3, 38.0, 44.2, 44.9, 48.0,123.1, 126.5, 126.9, 127.2, 135.3, 137.3, 169.6.

N-t-Butyl2-[3-bromo-2-oxo-5-cyclohexyl-2,3,4,5,-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared as a mixture of diastereomers, which separated into the lesspolar isomer, mp 188°-189.5° C., 36% yield, and the more polar isomer,mp 190.5°-192° C., 58% yield.

Less polar isomer:

¹ H-NMR (δ, CDCl₃): 0.4-2.0 (m, 11H), 1.36 (s, 9H), 2.39 (m, 1H), 2.61(m, 2H), 4.01 (AB_(q), J_(AB) =15, Dn=381, 2H), 4.59 (dd, J=8,12, 1H),6.25 (bs, 1H), 6.9-7.4 (m, 4H).

¹³ C-NMR (δ, CDCl₃): 26.1, 26.2, 28.7, 32.2, 32.5, 40.1, 42.5, 47.4,50.3, 51.5, 55.7, 124.7, 127.5, 128.6, 131.4, 136.0, 141.4, 167.6,168.6.

More polar isomer:

¹ H-NMR (δ, CDCl₃): 0.6-1.9 (m, 11H), 1.31 (s, 9H), 2.06 (m, 1H), 2.65(m, 2H), 4.26 (AB_(q), J_(AB) =15, Dn=32, 2H), 4.2 (m, 1H), 6.22 (bs,1H), 7.1-7.3 (m, 4H).

¹³ C-NMR (δ, CDCl₃): 26.0, 26.3, 26.4, 28.7, 30.3, 32.0, 37.7, 43.7,45.4, 48.1, 51.4, 54.8, 123.6, 126.1, 127.5, 127.6, 127.7, 136.2, 142.0,167.1, 168.4.

N-tert-butyl-2-[3-azido-2-oxo-5-cyclohexyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared from the more polar diastereomer in the previous step in 47%yield, mp 136°-139° C.

¹ H-NMR (δ, CDCl₃): 0.4-2.0 (m, 11H), 1.34 (s, 9H), 2.22 (m, 1H), 2.43(m, 2H), 3.84 (m, 1H), 4.04 (AB_(q), J_(AB) =15, Dn=291, 2H), 6.32 (bs,1H), 7.0-7.4 (m, 4H).

¹³ C-NMR (δ, CDCl₃): 26.0, 26.1, 26.2, 28.6, 32.2, 32.5, 36.6, 40.2,47.7, 51.5, 55.1, 58.4, 124.6, 127.4, 128.6, 131.3, 136.4, 140.7, 167.7,170.8.

N-tert-butyl-2-[3-amino-2-oxo-5-cyclohexyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared as a solid, mp 105°-115° C., in quantitative yield.

¹ H-NMR (δ, CDCl₃): 0.4-1.7 (m, 10H), 1.31 (s, 9H), 1.98 (m 1H), 2.18(m, 1H), 2.39 (m, 1H), 2.62 (m, 1H), 3.79 (m, 1H), 4.08 (AB_(q), J_(AB)=15, Dn=364, 2H), 5.5 (bs, 2H), 6.61 (bs, 1H), 7.0-7.3 (m, 4H).

¹³ C-NMR (δ, CDCl₃): 25.9, 26.2, 28.7, 32.2, 32.3, 37.7, 39.9, 47.9,50.6, 51.7, 54.1, 124.1, 127.3, 128.5, 131.6, 136.6, 140.4, 167.7,172.1.

N-tert-butyl-2-[3-(3-(3-tolyl)ureido)-2-oxo-5-cyclohexyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared as a white solid, mp 225°-228° C., 67% yield.

¹ H-NMR (δ, CDCl₃): 0.54 (m, 1H), 0.8-1.8 (m, 9H),1.35 (s, 9H), 2.0-2.2(m, 2H), 2.49 (m, 1H), 2.64 (m, 1H), 4.17 (AB_(q), J_(AB) =16, Dn=408,2H), 4.52 (m, 1H), 6.23 (d, J=7, 1H), 6.28 (s, 1H), 6.7-7.3 (m, 8H),7.62 (s, 1H).

¹³ C-NMR (δ, CDCl₃): 21.4, 26.1, 26.2, 26.3, 28.7, 32.3, 32.5, 37.6,40.4, 48.2, 50.6, 51.8, 54.0, 116.8, 120.5, 123.4, 123.5, 127.3, 128.4,128.5, 128.6, 131.7, 136.7, 138.6, 139.0, 140.9, 155.5, 167.5, 174.1.

EXAMPLE 116N-tert-butyl-2-[3-(3-(3-chlorophenyl)ureido)-2-oxo-5-cyclohexyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared fromN-tert-butyl-2-[3-amino-2-oxo-5-cyclohexyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide as in Example 115 as a white solid, mp 223°-226° C., 48%yield.

¹ H-NMR (δ, CDCl₃): 0.52 (m, 1H), 0.8-1.8 (m, 9H), 1.37 (s, 9H), 1.98(m, 1H), 2.13 (m, 1H), 2.48 (m, 1H), 2.58 (m, 1H), 4.23 (AB_(q), J_(AB)=16, Dn=408, 2H), 4.48 (m, 1H), 6.28 (s, 1H), 6.39 (δ, J=7, 1H), 6.8-7.3(m, 7H), 7.55 (s, 1H), 8.01 (s, 1H).

¹³ C-NMR (δ, CDCl₃): 26.1, 26.2, 28.7, 32.3, 32.5, 37.2, 40.3, 48.2,50.7, 52.1, 53.6, 116.9, 118.9, 119.0, 122.1, 123.0, 127.4, 128.6,129.4, 131.8, 134.2, 136.6, 140.5, 140.7, 155.2, 167.4, 174.5.

EXAMPLE 117N-tert-butyl-2-[3-(3-(3-ethylphenyl)ureido)-2-oxo-5-cyclohexyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide

Prepared fromN-tert-butyl-2-[3-amino-2-oxo-5-cyclohexyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoicacid amide as in Example 115 as a white solid, mp 145°-155° C., 61%yield.

¹ H-NMR (δ, CDCl₃): 0.48 (m, 1H), 0.7-1.7 (m, 9H), 1.30 (t, J=7.5, 3H),1.35 (s, 9H), 1.9-2.1 (m, 2H), 2.47 (q, J=7.5, 2H), 2.62 (m, 1H), 4.16(AB_(q), J_(AB) =16, Dn=404, 2H), 4.50 (m, 1H), 6.23 (d, J=7, 1H), 6.26(s, 1H), 6.7-7.3 (m, 8H), 7.63 (s, 1H).

¹³ C-NMR (δ, CDCl₃): 15.6, 26.1, 26.2, 26.3, 28.7, 28.9, 32.3, 32.5,37.7, 40.4, 48.2, 50.5, 51.8, 54.1, 117.1, 119.4, 119.5, 122.4, 123.4,123.5, 127.3, 128.5, 128.7, 131.7, 136.7, 139.0, 140.9, 145.1, 155.4,167.6, 176.0.

EXAMPLE 118 4-(4-Fluorophenyl)-4-hydroxycyclohexanone ethyleneketal

Prepared in analogy with J. Med. Chem., 1992, 35, 320-324 as follows: Toa 1 L round-bottomed flask equipped with N₂ inlet were added 46.8 g(0.30 mol) cyclohexane-1,4-dione monoethylene ketal and 500 mL drytetrahydrofuran. The solution was cooled to -78° C., and 150 mL of a2.0M solution (0.30 mol) of 4-fluorophenylmagnesium bromide in ether wasadded dropwise over 30 min, then the reaction was stirred for 10 min andwarmed to room temperature. The reaction was poured into ice/water, thelayers separated, and the aqueous phase extracted with ether. Thecombined organic phase was dried over sodium sulfate and evaporated to aan oil, which was triturated with ether to a white, low-melting solid,24.3 g (32%).

¹ H-NMR (δ, CDCl₃): 1.6-1.8 (m, 4H), 2.05 (m, 4H), 3.95 (bs, 4H), 6.96(m, 2H), 7.61 (m, 2H).

¹³ C-NMR (δ, CDCl₃): 30.7, 36.7, 64.2, 64.4, 72.1, 108.3, 114.8, 115.1,126.2, 126.3, 144.

MS (%): 234 (7, parent-H₂ O), 123 (15), 99 (100), 86 (60).

4-(4-Fluorophenyl)cyclohexanone

A solution of 5.0 g (19.8 mmol)4-(4-fluorophenyl)-4-hydroxycyclohexanone ethylene ketal in 170 mLdioxane was treated with 5.0 g 10% palladium-on-carbon under 35 p.s.i.hydrogen for 24 hr, then filtered through Celite to remove the catalyst.The filtrate was treated with 100 mL water and 3.5 mL concentratedhydrochloric acid, and stirred at room temperature for 24 hr. Thesolution was evaporated, the pH adjusted to 8 with saturated aqueoussodium bicarbonate solution, and extracted with methylene chloride. Theorganic layer was dried over sodium sulfate and evaporated. The residuewas chromatographed on silica gel using methylene chloride as eluant toafford 2.9 g (74%) of an oil.

¹ H-NMR (δ, CDCl₃): 1.83 (m, 2H), 2.12 (m, 2H), 2.42 (m, 4H), 2.96 (m,1H), 6.8-7.2 (m, 4H).

¹³ C-NMR (δ, CDCl₃): 34.1, 35.1, 41.3, 42.0, 115.2, 115.5, 128.0, 128.1,140.4, 140.5, 159.9, 163.1, carbonyl carbon not visible in this scan.

IR (cm.⁻¹, CHCl₃): 1705 (C═O).

MS (%): 192 (90), 135 (60), 122 (100), 109 (65), 57 (15).

HRMS Calc'd. for C₁₂ H₁₃ FO: 192.0947. Found: 192.0983. The remainder ofthe synthesis was carried out as described in Example 60:

2-Chloro-4-(4-fluorophenyl)cyclohexanone

Prepared as an oil in 93% yield.

¹ H-NMR (δ, CDCl₃): 1.9-3.7 (series of multiplets, 7H), 4.67 and 5.34(multiplets, 1H), 6.8-7.2 (m, 4H).

¹³ C-NMR (δ, CDCl₃): 33.4, 33.9, 34.3, 35.9, 40.4, 42.8, 45.5, 63.2,115.5, 115.7, 128.0, 128.1, 128.2, 128.3, carbonyl carbon not visible inthis scan.

MS (%): 226 (55, parent), 171 (85), 122 (100), 109 (95), 55 (45).

2-Phenyl-4-(4-fluorophenyl)cyclohexanone

Prepared as an oil in 29% yield.

¹ H-NMR (δ, CDCl₃): 2.0-2.4 (m, 4H), 2.64 (m, 2H), 33.24 (m, 1H), 3.79(dd, J=5,13, 1H), 6.9-7.4 (m, 9H).

MS (%): 268 (100, parent), 224 (90), 135 (65), 122 (95), 109 (75), 91(99).

2-Phenyl-4-(4-fluorophenyl)cyclohexanone oxime

Prepared as a light yellow solid, mp 192°-194° C., in 64% yield.

¹ H-NMR (δ, DMSO-d₆): 1.5-2.2 (m, 4H), 3.02 (m, 1H), 3.42 (m, 1H), 3.66(dd, J=4,13, 1H), 7.0-7.3 (m, 9H).

¹³ C-NMR (δ, DMSO-d₆): 24.1, 32.7, 41.3, 42.3, 48.3, 114.9, 115.1,126.0, 127.7, 128.5, 128.6, 128.9, 141.5, 142.0, 158.7, 159.12, 162.3.

5-(4-Fluorophenyl)-7-phenyl-hexahydroazepin-2-one

Prepared as a light yellow foam in 53% yield.

¹ H-NMR (δ, CDCl₃): 1.8-2.2 (m, 4H), 2.70 (m, 2H), 2.93 (m, 1H), 4.58(m, 1H), 5.72 (bs, 1H) NH), 6.9-7.4 (m, 9H).

¹³ C-NMR (δ, CDCl₃): 30.5, 36.2, 45.4, 46.2, 47.8, 58.0, 115.3, 115.6,115.7, 116.0, 125.5, 126.3, 127.6, 128.0, 128.4, 129.2, 141.8, 141.9,163.1, 176.4.

FAB MS (%): 284 (100, parent+1), 180 (37), 109 (10), 91 (11).

3-Bromo-5-(4-fluorophenyl)-7-phenyl-hexahydroazepin-2-one

Prepared as a mixture of diastereomers as a foam in 63% yield.

¹ H-NMR (δ, CDCl₃): 2.0-2.6 (m, 4H), 3.12 (m, 1H), 4.50 (m, 1H), 4.86and 4.98 (multiplets for the diastereomers at the 3-position, 1H), 5.87(bs, 1H) NH), 6.9-7.4 (m, 9H).

¹³ C-NMR (δ, CDCl₃): 42.0, 42.6, 44.1, 46.2, 47.2, 50.3, 57.3, 57.6,59.1, 115.5, 115.8, 126.2, 128.0, 128.1, 128.8, 129.4, 140.1, 141.0,160.1, 163.3, 169.6.

IR (cm.⁻¹, KBr): 1670 (C═O).

N-(t-Butyl)-2-oxo-3-bromo-5-(4-fluorophenyl)-7-phenyl-hexahydroazepin-1-ylethanoic amide

Prepared as a mixture of diastereomers as a foam in 73% yield.

¹ H-NMR (δ, CDCl₃): 1.27 and 1.29 (singlets for the two diastereomers,9H), 2.0-2.6 (m, 4H), 3.1 (m, 1H), 3.56 (m, 1H), 5.02 (m, 1H), 5.44 (m,1H), 6.9-7.3 (m, 9H).

N-(t-Butyl)-2-oxo-3-azido-5-(4-fluorophenyl)-7-phenyl-hexahydroazepin-1-ylethanoic amide

Prepared as a mixture of diasterteomers as a foam in 77% yield.

¹ H-NMR (δ, CDCl₃): 1.28 and 1.36 (singlets, 9H), 2.0-2.3 (m, 3H), 2.5(m, 1H), 3.10 (m, 1H), 3.51 and 3.79 (AB_(q) 's, J_(AB) =15, Dn=238 and326, 2H), 4.1 and 4.52 (multiplets, 1H), 4.90 and 5.09 (multiplets, 1H),5.50 and 5.90 (singlets, 1H), 6.9-7.5 (m, 9H).

¹³ C-NMR (δ, CDCl₃): 28.7, 28.8, 37.1, 37.6, 39.2, 40.5, 45.4, 48.3,51.5, 52.1, 60.9, 61.2, 62.0, 115.5, 115.8, 125.9, 128.1, 128.3, 128.4,128.8, 129.0, 129.4, 137.9, 140.1, 167.5, 170.7, 172.2.

N-(t-Butyl)-2-oxo-3-amino-5-(4-fluorophenyl)-7-phenyl-hexahydroazepin-1-ylethanoic amide

Prepared as a foam in 34% yield.

¹ H-NMR (δ, CD₃ OD): 1.21 (s, 9H), 2.0-2.3 (m, 3H), 2.70 (m, 1H), 3.30(bs over a multiplet, 3H), 3.73 (AB_(q), J_(AB) =17, Dn=178, 2H), 4.80(d, J=11, 1H), 5.23 (d, J=11, 1H), 6.9-7.4 (m, 9H).

N-(t-Butyl)-2-oXo-3-(3-tolylureido)-5-(4-fluorophenyl)-7-phenyl-hexahydroazepin-1-ylethanoic amide

Prepared as an amorphous solid in 62% yield.

¹ H-NMR (δ, CDCl₃,TFA): 1.20 (s, 9H), 1.9-2.4 (m, 4H), 2.33 (s, 3H),3.26 (m, 1H), 3.8-4.0 (m, 3H), 5.23 (m, 1H), 5.37 (m, 1H), 6.9-7.5 (m,15H).

EXAMPLE 119N-(t-Butyl)-2-oxo-3-(3-chlorophenylureido)-5-(4-fluorophenyl)-7-phenyl-hexahydroazepin-1-ylethanoic amide

Prepared fromN-(t-butyl)-2-oxo-3-amino-5-(4-fluorophenyl)-7-phenyl-hexahydroazepin-1-ylethanoic amide as in Example 118 as an amorphous solid in 54.5% yield.

¹ H-NMR (δ, CDCl₃,TFA): 1.20 (s, 9H), 2.00 (m, 1H), 2.2-2.5 (m, 3H),3.29 (m, 1H), 3.86 (m, 1H), 3.91 (AB_(q), J_(AB) =16, Dn=42, 2H), 5.25(d, J=11, 1H), 5.41 (d, J=11, 1H), 6.9-7.4 (m, 15H).

EXAMPLE 120N-(t-Butyl)-2-oxo-3-(3-methoxyphenylureido)-5-(4-fluorophenyl)-7-phenyl-hexahydroazepin-1-ylethanoic amide

Prepared fromN-(t-butyl)-2-oxo-3-amino-5-(4-fluorophenyl)-7-phenyl-hexahydroazepin-1-ylethanoic amide as in Example 118 as an amorphous solid in 55% yield.

¹ H-NMR (δ, CDCl₃,TFA): 1.19 (s, 9H), 1.97 (m, 1H), 2.2-2.5 (m, 3H),3.29 (m, 1H), 3.82 (s, 3H), 3.83 (m, 1H), 3.92 (AB_(q), J_(AB) =17,Dn=51, 2H), 5.23 (d, J=11, 1H), 5.38 (d, J=11, 1H), 6.7-7.4 (m, 15H).

I claim:
 1. A compound of the formula ##STR5## wherein Y¹ and Y² areindependently selected from the group consisting of phenyl, thienyl,pyridyl, furyl, pyrimidyl, (C₃ -C₈) straight or branched alkyl and (C₅-C₈) cycloalkyl, wherein said phenyl, thienyl, pyridyl, furyl andpyrimidyl may optionally substituted with one or two substituentsindependently selected from the group consisting of halo (C₁ -C₆) alkyl,(C₁ -C₆) alkoxy, nitro, amino and trifluoromethyl, and wherein saidcycloalkyl may optionally be substituted with one or two substituentsindependently selected from (C₁ -C₆) alkyl;Z¹ and Z² are independentlyselected from the group consisting of halo, (C₁ -C₆) alkyl, (C₁ -C₆)thioalkyl, (C₁ -C₆) alkoxy, trifluoromethyl, (C₁ -C₆) carboalkoxy, aminoand nitro; R¹ is phenyl, CO₂ R², SO₂ NR³ R⁶ or CONR⁴ R⁵, wherein saidphenyl may optionally be substituted with one or two substituentsindependently selected from the group consisting of halo, (C₁ -C₆)alkyl, (C₁ -C₆) alkoxy, nitro, amino and trifluoromethyl, and whereinR², R³, R⁴ and R⁵ are independently selected from hydrogen, (C₃ -C₁₂)alkyl and fused, saturated, carbocyclic systems containing two or threerings; or a pharmaceutically acceptable salt thereof R¹ is phenyl, CO₂R², SO₂ NR³ R⁶ or CONR⁴ R⁵, wherein said phenyl may optionally besubstituted with one or two substituents independently selected from thegroup consisting of halo, (C₁ -C₆) alkyl, (C₁ -C₆) alkoxy, nitro, aminoand trifluoromethyl, and wherein R², R³, R⁴ and R⁵ are independentlyselected from hydrogen, (C₃ -C₁₂) alkyl and fused, saturated,carbocyclic systems containing two or three rings; or a pharmaceuticallyacceptable salt thereof.
 2. A compound according to claim 1, whereinsaid compound is a compound of the formula I wherein either both of Y¹and Y² are phenyl or one of Y¹ and Y² is cyclohexyl, or apharmaceutically acceptable salt of said compound.
 3. A compoundaccording to claim 1, wherein said compound is selected from the groupconsistingof:3-((3-chlorophenyl)ureido)-7-cyclohexyl-(N-t-butoxycarbonylmethyl)-hexahydroazepin-2-one;3-((3-tolyl)ureido)-7-cyclohexyl-(N-t-butoxycarbonylmethyl)hexahydroazepin-2-one;3-((3-chlorophenyl)ureido)-7-cyclohexyl-(N-1-adamantyloxycarbonylmethyl)-hexahydroazepin-2-one;3-((3-chlorophenyl)ureido)-7-cyclohexyl-(N-2-adamantyloxycarbonylmethyl)-hexahydroazepin-2-one;3-((3-tolyl)ureido)-7-cyclohexyl-(N-1-adamantyloxycarbonylmethyl)-hexahydroazepin-2-one;3-((3-tolyl)ureido)-7-cyclohexyl-(N-2-adamantyloxycarbonylmethyl)-hexahydroazepin-2-one;3-((3-methoxyphenyl)ureido)-7-cyclohexyl-(N-t-butoxycarbonylmethyl)-hexahydroazepin-2-one;3-((3-methoxyphenyl)ureido)-7-cyclohexyl-(N-1-adamantyloxycarbonylmethyl)-hexahydroazepin-2-one;3-((3-methoxyphenyl)ureido)-7-cyclohexyl-(N-2-adamantyloxycarbonylmethyl)-hexahydroazepin-2-one;3-((3-chlorophenyl)ureido)-5,7-diphenyl-(N-t-butoxycarbonylmethyl)-hexahydroazepin-2-one;3-((3-tolyl)ureido)-5,7-diphenyl-(N-t-butoxycarbonylmethyl)-hexahydroazepin-2-one;3-((3-methoxyphenyl)ureido)-5,7-diphenyl-(N-t-butoxycarbonylmethyl)-hexahydroazepin-2-one;3-((3-chlorophenyl)ureido)-5,7-diphenyl-(N-1-adamantyloxycarbonylmethyl)-hexahydroazepin-2-one;N-tert-butyl-2-[2-oxo-3-((3-tolyl)ureido)-5,7-diphenyl-hexahydroazepin-1-yl]-ethanoicacid amide;N-tert-butyl-2-[2-oxo-3-((3-chlorophenyl)ureido)-5,7-diphenylhexahydroazepin-1-yl]ethanoicacid amide;N-tert-butyl-2-[2-oxo-3-((3-methoxyphenyl)ureido)-5,7-diphenylhexahydroazepin-1-yl]ethanoicacid amide;N-tert-butyl-2-[2-oxo-3-((3-trifluoromethylphenyl)ureido)-5,7-diphenylhexahydroazepin-1-yl]ethanoicacid amide;N-tert-butyl-2-[2-oxo-3-((3-methylthiophenyl)ureido)-5,7-diphenyl-hexahydroazepin-1-yl]ethanoicacid amide;N-tert-butyl-2-[2-oxo-3-((3-cyanophenyl)ureido)-5,7-diphenyl-hexahydroazepin-1-yl]ethanoicacid amide;N-tert-butyl-2-[2-oxo-3-((3-dimethylaminophenyl)ureido)-5,7-diphenyl-hexahydroazepin-1-yl]ethanoicacid amide; andN-tert-butyl-2-[2-oxo-3-((3-ethylphenyl)ureido)-5,7-diphenyl-hexahydroazepin-1-yl]ethanoicacid amide.
 4. A pharmaceutical composition for treating or preventing acondition selected from the group consisting of pain, gastrointestinaldisorders such as ulcer and colitis, and central nervous systemdisorders such as anxiety and panic disorder in a mammal, comprising anamount of a compound according to claim 1 effective in preventing ortreating such condition and a pharmaceutically acceptable carrier.
 5. Amethod of treating or preventing a condition selected from the groupconsisting of pain, gastrointestinal disorders such as ulcer andcolitis, and central nervous system disorders such as anxiety and panicdisorder in a mammal, comprising administering to a mammal in need ofsuch treatment or prevention an amount of a compound according to claim1 effective in treating or preventing such condition.
 6. Apharmaceutical composition for antagonizing the effects ofcholecystokinin in a mammal, comprising a CCK-B antagonizing effectiveamount of a compound according to claim 1 and a pharmaceuticallyacceptable carrier.
 7. A method of antagonizing the effects ofcholecystokinin in a mammal, comprising administering to said mammal aCCK-B antagonizing effective amount of a compound according to claim 1.